@article {pmid42413935,
year = {2026},
author = {Lee, S and Kao, CY and Li, Z and Dan, T and Wu, G and Hao, W},
title = {Optimal control for anti-abeta treatment in Alzheimer's disease using a reaction-diffusion model.},
journal = {Journal of the Royal Society, Interface},
volume = {23},
number = {240},
pages = {},
doi = {10.1098/rsif.2025.1158},
pmid = {42413935},
issn = {1742-5662},
support = {1R35GM146894/GF/NIH HHS/United States ; DMS-2533995//NSF/ ; DMS 2208373//NSF/ ; DMS 2513176//NSF/ ; //Huck Chair in AI Mathematical Modeling from Penn State University's Huck Institutes of the Life Sciences/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Models, Biological ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely impairs survival and quality of life. While anti-amyloid beta (Aβ) therapies can slow disease progression, their efficacy depends on personalized dosing that maximizes benefits and minimizes risks, such as amyloid-related imaging abnormalities (ARIA). Mathematical modelling offers a powerful tool for understanding AD dynamics and optimizing treatment, yet most models focus solely on temporal behaviour, overlooking spatial heterogeneity within the brain. In this study, we propose a spatially explicit reaction-diffusion model to describe Aβ plaque dynamics. We formulate an optimal control problem to minimize plaque concentration while balancing therapeutic efficacy and treatment risk. Under reasonable assumptions, we establish well-posedness and uniqueness of the optimal solution. A finite element method (FEM)-based numerical framework is developed to compute personalized treatment strategies. Our model is calibrated using longitudinal Aβ positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), enabling estimation of patient-specific parameters, such as growth rate and effective diffusivity. Results show that optimized treatment strategies consistently outperform constant dosing regimens across patient groups, achieving substantial reductions in cumulative amyloid burden while minimizing side effects. This integrated, data-driven framework advances personalized, spatially informed therapeutic optimization for AD.},
}

*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy
Humans
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Models, Biological
Positron-Emission Tomography

@article {pmid42415176,
year = {2026},
author = {Eom, JW and Kim, KR and Kim, DH and Song, JG and Han, C and Kim, HW and Ha, S and Song, WJ and Kim, YH},
title = {Zinc-mediated lysosomal activation by 1H10 enhances autophagy and attenuates tau pathology in Alzheimer's disease models.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01328-9},
pmid = {42415176},
issn = {1756-6606},
support = {NRF-2020R1I1A1A01061724//National Research Foundation of Korea/ ; RS-2023-NF001356//National Research Foundation of Korea/ ; 2025-RISE-01-019-04//The seoul RISE centor/ ; },
abstract = {Impaired autophagic flux and lysosomal dysfunction contribute critically to the accumulation of pathological protein aggregates in Alzheimer's disease (AD). Emerging evidence suggests that intracellular zinc dynamics regulate lysosomal function by modulating processes such as acidification and lysosomal biogenesis. We previously identified 1H10 as an AMP-activated protein kinase (AMPK) inhibitor and subsequently demonstrated its zinc-binding capacity and ability to regulate intracellular zinc homeostasis. Building on our prior findings that intra-lysosomal zinc promotes acidification and activates transcription factor EB (TFEB), we investigated whether 1H10 enhances lysosomal function through zinc mobilization in neurons, thereby improving autophagy and reducing pathological protein accumulation. In primary cortical neurons, 1H10 increased lysosomal abundance and enhanced lysosomal degradative capacity in a zinc-dependent manner, as demonstrated by increased cathepsin B activity and DQ-BSA degradation. It alleviated lysosomal dysfunction induced by v-ATPase inhibition and promoted autophagic flux, leading to reduced accumulation of amyloid-β (Aβ) and tau in neuronal models. In 5XFAD mice, 1H10 treatment showed trends toward improved spatial learning in the Morris water maze, reduced tau phosphorylation at Thr205 and Ser214, normalized LC3-II levels, and restored autophagic-lysosomal homeostasis, without significant changes in extracellular amyloid plaque burden. These findings indicate that zinc-mediated lysosomal activation by 1H10 enhances the autophagy-lysosomal pathway and attenuates tau pathology in AD models, suggesting that targeting lysosomal function may represent a potential therapeutic strategy for neurodegenerative disorders characterized by impaired proteostasis.},
}

@article {pmid42415281,
year = {2026},
author = {Aldana, BI and Freude, K},
title = {Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {139},
number = {2},
pages = {e70273},
pmid = {42415281},
issn = {1742-7843},
support = {R434-2023-242//Lundbeck Foundation/ ; N/A//Alzheimersfonden/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Chemokines/metabolism/immunology ; Animals ; Female ; Male ; Sex Factors ; Signal Transduction ; Virus Diseases/immunology ; Neuroinflammatory Diseases/immunology ; COVID-19/immunology ; Receptors, Chemokine/metabolism ; Brain/immunology/metabolism ; Sex Characteristics ; },
abstract = {Chemokines constitute a versatile signalling network maintaining homeostasis and glia-neuron communication in the healthy brain but become progressively dysregulated during aging and Alzheimer's disease (AD). This review examines how chemokine systems transition from tightly regulated homeostatic signals to drivers of chronic neuroinflammation in AD. We describe the major chemokine families (CC, CXC, CX3C) and their dominant central nervous system (CNS) receptors (CCR2, CXCR3, CX3CR1), which activate canonical inflammatory pathways including NF-κB, JAK/STAT and PI3K-AKT. In AD, chemokine dysregulation occurs in a coordinated manner across multiple functional modules, including recruitment-associated (CCL2, CXCL1), interferon-inducible (CXCL10), loss-of-restraint (CX3CL1) and vascular-associated chemokines. These alterations shift the network from regulated immune communication to self-sustaining inflammatory circuits perpetuating chronic neuroinflammation. These networks reprogram microglia and astrocytes into disease-associated phenotypes, amplify peripheral immune cell infiltration and destabilise synaptic function. Biological sex profoundly influences neuroinflammatory trajectories, with females exhibiting enhanced microglial senescence and interferon signalling, while males show accelerated complement activation. Viral pathogens, particularly neurotropic viruses (HSV-1, HHV-6, VZV) and SARS-CoV-2, actively reprogram chemokine networks, linking infection to amyloid-β accumulation, tau pathology and neurodegeneration. Therapeutically, chemokine axes represent precision targets requiring stage-matched, sex-stratified interventions rather than broad anti-inflammatory approaches. Understanding chemokine network dynamics offers mechanistic insights into AD pathogenesis and could provide pointers for therapeutic strategies.},
}

Humans
*Alzheimer Disease/immunology/metabolism
*Chemokines/metabolism/immunology
Animals
Female
Male
Sex Factors
Signal Transduction
Virus Diseases/immunology
Neuroinflammatory Diseases/immunology
COVID-19/immunology
Receptors, Chemokine/metabolism
Brain/immunology/metabolism
Sex Characteristics

@article {pmid42415688,
year = {2026},
author = {Hill, N and AlMuallim, HYO and Maddock, E and Hobbs, C and Clarke, E and Goncalves, MB and Corcoran, JPT},
title = {Treatment with KCL-286, a first-in-class retinoic acid receptor-β (RARβ) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer's disease.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70284},
pmid = {42415688},
issn = {2211-5463},
support = {110047/Z/15/Z/WT/WT_/Wellcome Trust/United Kingdom ; MR/R006466/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which effective disease-modifying therapies remain limited. Accumulation of neuronal DNA double-strand breaks (DSBs) is an early pathological event that contributes to genomic instability and neuronal vulnerability in AD. Therapeutic strategies that enhance DNA repair may therefore be of considerable interest. Here, using the Tg2576 mouse model of AD, we show that treatment with KCL-286, a selective retinoic acid receptor-β (RARβ) agonist, reduces neuronal DNA damage. KCL-286 enhances DSB repair in neurons, in part through upregulation of the DNA repair factor BRCA1, while also attenuating neuroinflammatory activation. In addition, KCL-286 normalises microglial and astrocytic morphology, consistent with reduced pathological glial activation. Together, these findings demonstrate that selective RARβ activation ameliorates neuronal DNA damage and neuroinflammation in a mouse model of AD, supporting further investigation as a potential disease-modifying therapeutic strategy.},
}

@article {pmid42415930,
year = {2026},
author = {Wang, PJ and Yang, XY and Ji, L and Shi, JJ and Cai, XM and Sun, P and Liu, HX and Jiang, F and Yang, F},
title = {Peripheral metabolomic profiling reveals lipid and amino acid alterations associated with immuno-inflammatory responses in treatment-naïve late-onset Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1858299},
pmid = {42415930},
issn = {1663-4365},
abstract = {BACKGROUND: Immuno-metabolic dysregulation contributes to Alzheimer's disease (AD) pathogenesis, yet the peripheral metabolic landscape and its interplay with neuroinflammation remain poorly characterized in treatment-naïve, late-stage patients. This study aimed to delineate plasma metabolic alterations and immuno-metabolic interactions in Chinese first-time outpatients with late-onset AD (CFTO-LOAD).

METHODS: Untargeted metabolomics and ELISA were applied to plasma from 35 CFTO-LOAD patients and 35 sex-matched cognitively healthy controls (CHCs) to quantify metabolites, cytokines (TNF-α, IL-17, IL-9), and soluble Aβ/Tau markers.

RESULTS: A total of 875 differentially abundant metabolites (DAMs) were identified in CFTO-LOAD, comprising 227 upregulated and 648 downregulated species (P < 0.05), predominantly lipids, fatty acids (e.g., dodecanoic acid, arachidonic acid), and amino acids (e.g., L-arginine, L-leucine). KEGG analysis revealed enrichment in fatty acid and amino acid metabolism, GABAergic synapse, and intestinal immune network pathways. CFTO-LOAD patients exhibited elevated pro-inflammatory cytokines TNF-α and IL-17 (P adj < 0.05), reduced IL-9 (P adj < 0.001), increased soluble p-Tau, p-Tau181, and p-Tau217 (P adj < 0.01), and decreased Aβ42/Aβ40 ratio (P adj < 0.001). Linear regression identified significant correlations between differential metabolites and immune/pathological markers, including positive associations of dodecanoic acid with TNF-α (r = 0.34, P adj < 0.05) and arachidonic acid with Aβ42/Aβ40 ratio (r = 0.30, P adj < 0.05), and negative associations of arachidonic acid with p-Tau217 (r = -0.43, P adj < 0.01) and sphinganine 1-phosphate with TNF-α (r = -0.28, P adj < 0.05).

CONCLUSION: These findings characterize the peripheral immuno-metabolic landscape in treatment-naïve late-onset AD, identifying metabolic mediators that may mechanistically link neuroinflammation to Aβ and Tau pathology. This provides a foundation for biomarker development and therapeutic targeting in late-stage disease, pending independent validation.},
}

@article {pmid42416049,
year = {2026},
author = {Yang, M and Liang, Z},
title = {GLP-1 receptor agonists in neurological diseases: mechanisms and therapeutic prospects from metabolism to neuroprotection.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839620},
pmid = {42416049},
issn = {1664-3224},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used metabolic therapies for type 2 diabetes and obesity, with well-established cardiovascular benefits. Beyond glycemic control, accumulating experimental and clinical evidence suggests that GLP-1RAs exert pleiotropic actions relevant to neurological diseases. Metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury represent convergent mechanisms that contribute to neurodegeneration, cerebrovascular pathology, and metabolism-related brain disorders. Notably, these processes overlap with pathways modulated by GLP-1 signaling across systemic and central compartments. GLP-1 receptors are expressed in neurons, glial cells, and components of the neurovascular unit, providing a biological basis for possible neurological effects. Preclinical studies suggest that GLP-1RAs can reduce neuroinflammation and oxidative stress, support mitochondrial function, and help maintain blood-brain barrier integrity. Clinical findings, however, remain inconsistent. Studies in Parkinson's disease have reported encouraging signals, but biomarker evidence for disease modification is still limited. In Alzheimer's disease, clinical trials have produced mixed or negative results. These differences may reflect disease stage, patient selection, drug-specific pharmacology, central nervous system exposure, endpoint sensitivity, and treatment duration. Overall, GLP-1RAs may influence neurological disease through metabolic, inflammatory, and vascular pathways, but their clinical role remains unsettled. Future studies should use biomarker-informed designs, prespecified neurological endpoints, appropriate drug selection, and sufficiently long follow-up to determine which patients and disease stages are most likely to benefit.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy/metabolism
Glucagon-Like Peptide-1 Receptor/metabolism
*Neuroprotection/drug effects
Oxidative Stress/drug effects

@article {pmid42418270,
year = {2026},
author = {Caselli, RJ and Geldmacher, DS and Schilling, TB},
title = {A Narrative Review of Amyloid-β Monoclonal Antibodies for Alzheimer Disease: How Amyloid Species Engagement May Affect Clinical Outcomes.},
journal = {The neurologist},
volume = {31},
number = {4},
pages = {129-135},
pmid = {42418270},
issn = {2331-2637},
support = {//Eli Lilly and Company, Indianapolis, IN/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Plaque, Amyloid/drug therapy ; Animals ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of death worldwide, with growing prevalence as life expectancy increases. An important neurological hallmark of AD is the deposition of extracellular neuritic amyloid-β (Aβ) plaques that can disrupt synaptic transmission and cause neuronal death. More recent studies suggest that targeting Aβ species can slow the progression of cognitive decline in AD.

REVIEW SUMMARY: This narrative review examines the efficacy of monoclonal antibodies targeting the amyloid-β (Aβ) protein in the treatment of AD. It discusses the mechanisms by which these antibodies aim to mitigate amyloid pathology and explores their clinical outcomes in various trials. The review highlights the importance of amyloid plaque reduction to less than 25 Centiloids observed through amyloid positron emission tomography (PET) scans as a predictor of slowing cognitive decline. The findings suggest that targeting insoluble amyloid plaques is crucial for achieving clinical benefits in AD treatment. This review also discusses the phenomenon of amyloid-related imaging abnormalities (ARIA) that may be associated with monoclonal antibody therapy.

CONCLUSION: Monoclonal antibodies that target Aβ monomers, soluble oligomers and protofibrils, and insoluble fibrils/plaques were developed, and not all have provided clinical benefit. Emerging evidence suggests that it is important to reduce amyloid plaque burden to less than 25 Centiloids, consistent with a visually negative amyloid PET scan, in order to slow cognitive decline in early symptomatic AD.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Amyloid beta-Peptides/immunology/metabolism
*Antibodies, Monoclonal/therapeutic use
Plaque, Amyloid/drug therapy
Animals

@article {pmid42418504,
year = {2026},
author = {Cai, Y and Wang, Y and Huang, W and Su, Y and Lei, M and Jia, R and Wu, C and Zhang, T and Sun, L and Peng, B and Cheng, J and Yu, J and Chen, X and Ye, Q and Yu, J and Xin, J},
title = {Lecanemab treatment improves B cell subpopulation immune homeostasis in patients with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71655},
pmid = {42418504},
issn = {1552-5279},
support = {82571602//National Natural Science Foundation of China/ ; 82371188//National Natural Science Foundation of China/ ; 2022ZD0211603//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; ADB510200//Lingang Laboratory/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology ; *Homeostasis/drug effects ; Female ; Male ; *B-Lymphocyte Subsets/drug effects/immunology ; Aged ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *B-Lymphocytes/drug effects/immunology ; Leukocytes, Mononuclear/drug effects ; },
abstract = {INTRODUCTION: Lecanemab, the first disease-modifying therapy for Alzheimer's disease (AD), mitigates pathology primarily by clearing amyloid plaques, but its impact on peripheral immunity remains unclear.

METHODS: To assess Lecanemab's immunological effects, we performed antibody array analysis of serum and single-cell RNA sequencing of peripheral blood mononuclear cells collected from healthy controls and patients with AD at baseline, 3, and 6 months post-treatment.

RESULTS: Lecanemab restored multiple serum chemokines to healthy levels in patients with AD. Compared to controls, baseline samples from patients with AD showed altered frequencies and functions of naïve and unswitched memory (UswM) B cells. Lecanemab treatment corrected the abnormal naïve and UswM B cell proportions and rebuilt their functional homeostasis by alleviating chronic inflammation and reversing the dysregulation of key pathways including immune response, NF-κB, RAGE, and cell adhesion.

DISCUSSION: These findings uncover a novel peripheral immunomodulatory mechanism of Lecanemab, offering new insights into AD therapeutics.},
}

Humans
*Alzheimer Disease/drug therapy/immunology
*Homeostasis/drug effects
Female
Male
*B-Lymphocyte Subsets/drug effects/immunology
Aged
*Antibodies, Monoclonal/therapeutic use/pharmacology
*B-Lymphocytes/drug effects/immunology
Leukocytes, Mononuclear/drug effects

@article {pmid42419633,
year = {2026},
author = {Cauzzi, E and Ficchì, S and De Paolis, ML and Saba, L and Montanari, M and Loffredo, G and La Barbera, L and Krashia, P and Nobili, A and D'Amelio, M},
title = {Midbrain dopamine loss drives parvalbumin interneuron vulnerability through tissue plasminogen activator-linked perineuronal-net breakdown and hippocampal disinhibition.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107527},
doi = {10.1016/j.nbd.2026.107527},
pmid = {42419633},
issn = {1095-953X},
abstract = {Midbrain dopaminergic degeneration is an early feature of Alzheimer's Disease (AD), dementia with Lewy bodies (DLB), and AD-Parkinson's disease overlap (AD-PD). However, its direct contribution to the failure of hippocampal inhibitory-circuits, a pathological feature shared across these conditions, remains unresolved. Parvalbumin-positive interneurons (PV-INs) regulate hippocampal excitation-inhibition balance and are directly modulated by dopamine (DA). These neurons are protected by perineuronal nets (PNNs), extracellular-matrix structures supporting fast GABAergic signaling and neuronal resilience. We tested whether midbrain-derived DA loss is sufficient to destabilize hippocampal PV-IN function, potentially promoting their vulnerability or affecting PNN integrity. Through stereotaxic unilateral 6-hydroxy-dopamine lesion of the Ventral Tegmental Area/Substantia Nigra pars compacta in C57BL/6 N mice, we reduced the hippocampal DA tone and midbrain-derived synaptic input onto PV-INs. At 1-month post-lesion, PV-IN numbers were preserved, but the PNN integrity was reduced, accompanied by increased expression of tissue plasminogen activator (tPA), a PNN-remodeling protease. In CA1 pyramidal neurons, spontaneous inhibitory postsynaptic currents showed reduced frequency with faster decay, and bicuculline unmasked heightened population-spike excitability. By 6-months post-lesion, PV-IN numbers declined significantly, especially in CA1, demonstrating progressive vulnerability. D2/D3 receptor (D2/D3R) activation with quinpirole normalized tPA levels in PV-INs ex vivo, restored PNN integrity after sub-chronic treatment in vivo and increased inhibitory postsynaptic-event frequency, indicating functional recovery of GABAergic drive. These findings support the involvement of a DA-D2/D3R-tPA axis contributing to PV-IN extracellular-matrix integrity and hippocampal inhibitory tone. They also demonstrate that DA depletion is sufficient to trigger PNN breakdown, reduce GABAergic inhibition, network hyperexcitability, and cause progressive PV-IN loss independently of canonical protein aggregates like Aβ, tau or α-synuclein, characteristic of AD, DLB or AD-PD. This mechanism links midbrain degeneration to hippocampal circuit failure, highlighting D2/D3R signaling and extracellular proteolysis as actionable targets for early circuit stabilization across AD, DLB, and AD-PD.},
}

@article {pmid42420256,
year = {2026},
author = {He, CY and Wang, XY and Fan, J and Wang, YN and Masters, CL and Wang, YJ},
title = {Could the cognitive benefits of amyloid-beta clearance grow in time for Alzheimer's disease?.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04188-y},
pmid = {42420256},
issn = {2158-3188},
support = {82588301//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82120108010//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82401695//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Alzheimer's disease (AD) is characterized histologically by amyloid-β (Aβ) deposition in the brain. Immunotherapies targeting Aβ clearance have become a leading treatment strategy. Although these therapies effectively reduce cerebral Aβ burden, their cognitive benefits remain modest during the trial period. This review systematically assesses the extent of Aβ clearance by immunotherapies and its related cognitive outcomes, focusing on whether cognitive benefits increase over time. We refine a model of the "lag effect" between plaque clearance and cognitive benefit, which is potentially influenced by clearance rate, treatment duration, disease stage, genetic factors, and aging. We also discuss the underlying biological mechanisms and potential neuroprotective targets. Future research should prioritize long-term studies, early intervention, personalized therapies, and combination approaches addressing multiple pathological pathways. Given limited short-term cognitive gains, optimizing outcomes will require tailoring treatments to individual patient factors-including genetics, disease progression, and aging-to minimize side effects and enhance long-term cognitive function.},
}

@article {pmid42420546,
year = {2026},
author = {Nour, H and Mounadi, N and Samadi, A and Chtita, S},
title = {Stylopine as multi-target anti-Alzheimer agent.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61364-2},
pmid = {42420546},
issn = {2045-2322},
support = {#12R282//Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University/ ; },
abstract = {Alzheimer's disease is a complex neurodegenerative disorder involving multiple enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), monoamine oxidase B (MAO-B), and β-secretase (BACE-1). Currently available treatments are limited to acetylcholinesterase inhibitors, which offer purely symptomatic relief and do not halt disease progression. Consequently, the development of multi-target ligands represents a promising therapeutic approach. In this study, Alkaloids were evaluated using in silico approaches. Predictions of biological activity performed using the PASS software revealed stylopine as a promising candidate with potential anti-Alzheimer activity. Furthermore, this compound demonstrated strong binding affinity for key targets (Torpedo AChE, BuChE, and BACE-1), as well as a promising pharmacokinetic profile. Molecular dynamics simulations and MM-GBSA calculations have demonstrated the stability of stylopine-target interactions. Taken together, these studies suggest that stylopine could be a promising multitarget agent for the treatment of Alzheimer's disease, although further experimental data are needed to confirm its efficacy.},
}

@article {pmid42421820,
year = {2026},
author = {Brosch, JR and Wang, S and Apostolova, LG and Agarwal, A and Allen, JW and Gutmann, L and Tobar, M and Gonzalez, L and Johnson, D and Treadway, L and Connolly, J and Tang, A and Lettich, E and Davies, S and Kuhn, N and Hammers, DB and Clark, D and Farlow, M and Willis, DR and Fowler, N and Wilcock, DM},
title = {The Indiana University Brain Health Program to deliver amyloid-targeted therapy to Alzheimer's disease patients.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70291},
pmid = {42421820},
issn = {2352-8737},
abstract = {INTRODUCTION: The Indiana University Brain Health Program was developed to support safe implementation of amyloid-targeting therapies (ATTs) for early Alzheimer's disease (AD).

METHODS: We established Neurology Brain Health Navigators (neuroBHNs) to extend our Brain Health Navigator model into specialty care. NeuroBHNs pre-screen patients for ATT eligibility, coordinate biomarker and imaging evaluation, provide structured education, and guide treatment initiation and monitoring. The program includes a dedicated social worker and insurance pre-authorization specialist to streamline infusion access. Blood pressure is monitored at each visit, and infusions are deferred if readings exceed 140/90 mmHg.

RESULTS: Through December 16, 2025, 243 patients initiated lecanemab therapy. Apolipoprotein E (APOE) ε4 homozygotes were not excluded; 74% of treated patients carried at least one Apoε4 allele. The ARIA rate was 13.2%, and 40% of patients experienced infusion-related reactions.

CONCLUSIONS: A navigator-centered model can efficiently deliver ATT while supporting structured education, screening, and safety monitoring, potentially contributing to favorable safety outcomes.},
}

@article {pmid42422111,
year = {2026},
author = {Wang, J and Fu, X and Liu, J and Yang, Y},
title = {Non-invasive brain stimulation in frontotemporal dementia: syndrome-specific signals and priorities for future trials.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1842455},
pmid = {42422111},
issn = {1663-4365},
abstract = {Frontotemporal dementia is the second most common cause of young-onset dementia after Alzheimer's disease and lacks disease-modifying treatment. This narrative review summarizes human studies of non-invasive brain stimulation, including repetitive transcranial magnetic stimulation and theta-burst stimulation, transcranial electrical stimulation, and transcranial photobiomodulation, in frontotemporal dementia and primary progressive aphasia. We review stimulation targets, protocols, outcomes, and safety, and organize the evidence by clinical subtype and modality. Current data remain preliminary, but recurrent signals support prefrontal and cerebellar repetitive transcranial magnetic stimulation/theta-burst stimulation and prefrontal or temporoparietal transcranial direct current stimulation, particularly in primary progressive aphasia. By contrast, controlled evidence in behavioral-variant frontotemporal dementia is limited and heterogeneous. Future trials should be sham-controlled, multicenter, and syndrome-stratified; combine stimulation with symptom-relevant cognitive or language therapy; and incorporate biomarker-informed targeting, target-engagement measures, and longer follow-up to determine durability and clinical relevance.},
}

@article {pmid42422228,
year = {2026},
author = {Sukreet, S and Donohue, MC and Ngolab, J and Belsha, A and Salazar, J and Cohen, P and Jaiswal, S and Tan, V and Aggarwal, NT and Alber, J and Johnson, K and Jicha, GA and van Dyck, CH and Ramanan, S and Lah, JJ and Salloway, S and Verdooner, SR and Rafii, MS and Aisen, PS and Sperling, RA and Rissman, RA},
title = {Relationships between longitudinal retinal amyloid imaging and amyloid PET in the A4 Trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70422},
pmid = {42422228},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with retinal amyloid-related changes, which may help identify amyloid positron emission tomography (PET) positive (+) individuals. Previously, in a small cross-sectional study, we reported higher retinal spot counts (RSCs) in preclinical amyloid PET (+) individuals screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial compared to control individuals enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) trial before drug treatment.

METHODS: Eligible volunteers had retinal scans 48 hours after consuming curcumin. Scans were processed and quantified via NeuroVision. Participants were grouped by amyloid status and treatment to assess the effect of solanezumab on RSC.

RESULTS: RSC did not differ significantly over time between groups and was not modified by treatment, diverging from the cross-sectional retinal amyloid findings observed in A4/LEARN.

DISCUSSION: Curcumin-based retinal amyloid labeling shows promise but needs standardized protocols and validation in larger cohorts to understand its relationship to amyloid PET.},
}

@article {pmid42422260,
year = {2026},
author = {Akhbari, M and Babaei, F and Navidi-Moghaddam, A and Ghafghazi, S and Khodabandehloo, F and Sarookhani, MR and Dargahi, L and Mohammadi, G and Nassiri-Asl, M},
title = {The effects of Saccharomyces boulardii on TLR4/NF-κB neuroinflammatory pathway in the hippocampus of LPS-induced rats.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {199-206},
pmid = {42422260},
issn = {2667-2421},
abstract = {Saccharomyces boulardii (Sb), a probiotic yeast, is known for its positive effects on gastrointestinal and metabolic health. Recent research has explored its potential to influence neurological conditions by modulating neuroinflammatory responses via the gut-brain axis. Toll-like receptor 4 (TLR4) is recognized as a key molecular target in regulating neuroinflammation, particularly in disorders like Alzheimer's disease (AD). This study investigated whether Sb could alleviate downstream elements of the TLR4 neuroinflammatory pathway in a lipopolysaccharide (LPS)-induced rat model relevant to AD. Rats were randomly assigned to four groups: 1) control, 2) LPS, 3) Sb + LPS, and 4) Sb alone. All groups received either normal saline or Sb (a volume of 1 ml containing 10 [10] CFU) by oral gavage for four weeks. From day 14, LPS (250 μg/kg/day) or saline was administered intraperitoneally for nine days. Researchers assessed spatial memory, levels of TLR4 pathway-associated proteins in the hippocampus, pro-inflammatory cytokine expression, and neuronal survival using Nissl staining. The results showed that pre-treatment with Sb partially ameliorated spatial learning deficits, significantly reducing the LPS-induced elevation of nuclear factor kappa B (NF-κB) and interleukin-1β (IL-1β) in the hippocampus and protecting against neuronal loss in the hippocampal CA1 region. Sb mitigates LPS-induced neuroinflammation by modulating downstream elements of the TLR4 pathway-specifically NF-κB and IL-1β-rather than acting directly on the TLR4 receptor, likely through mechanisms involving the gut-brain axis.},
}

@article {pmid42411221,
year = {2026},
author = {Sharma, A and Kaur, A and Khan, J and Pandey, H},
title = {Phyto-Nanotherapeutics for Alzheimer's Disease: Current Progress and Future Perspectives.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249455878260609100548},
pmid = {42411221},
issn = {1875-6166},
abstract = {Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive and behavioral impairment and represents a major cause of dementia worldwide. It primarily affects the elderly population. The disease is marked by progressive neuronal damage, leading to impairments in cognition, behavior, emotions, and communication. Although currently available therapies provide symptomatic relief, they fail to alter disease progression, necessitating the development of more effective therapeutic strategies. Phytoconstituents have gained considerable attention due to their neuroprotective properties and multitargeted mechanisms of action against pathways implicated in AD. However, their clinical application is limited by poor Blood-Brain Barrier (BBB) permeability, low bioavailability, and inadequate solubility. Nanotechnology offers a promising approach for brain-targeted drug delivery by enhancing the therapeutic efficacy of phytoconstituents through advanced nanocarrier systems. This review explores the synergistic potential of phytoconstituents and nanocarriers for the management of AD, aiming to improve therapeutic outcomes and overcome existing limitations. It further highlights the integration of medicinal plant-based compounds with nanotechnology as a novel strategy for AD treatment. The combination of nanocarriers and phytoconstituents may facilitate enhanced BBB penetration and improved neuroprotection. Notably, nanomedicine- based approaches, including phytoconstituent-loaded nanoparticles and liposomes, demonstrate significant potential to overcome delivery barriers and enable efficient drug transport to the brain.},
}

@article {pmid42411440,
year = {2026},
author = {Ye, T and Shuai, Y and Liu, Y and Liu, S and Tang, X and Tian, W and Zhang, Y and Kong, Y},
title = {Efficacy and Safety of Transcranial Direct Current Stimulation on Multiple Health Outcomes in Neurological Disorders: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {6},
pages = {47145},
doi = {10.31083/JIN47145},
pmid = {42411440},
issn = {0219-6352},
mesh = {*Transcranial Direct Current Stimulation ; Humans ; *Nervous System Diseases/therapy ; *Randomized Controlled Trials as Topic ; Meta-Analysis as Topic ; Systematic Reviews as Topic ; *Outcome Assessment, Health Care/statistics & numerical data ; },
abstract = {BACKGROUND: Neurological disorders are a leading cause of disability worldwide. Transcranial direct current stimulation (tDCS) is a promising therapeutic tool for neurological disorders. However, a consensus on clinical recommendations for using tDCS in patients with neurological disorders is lacking. In this umbrella review, we aimed to establish evidence-based guidance for using tDCS to treat neurological disorders.

METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020. PubMed/MEDLINE, Embase, the Cochrane Library, the Web of Science, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were systematically searched to identify and evaluate existing systematic reviews and meta-analyses on the use of tDCS for neurological disorders. Quality was assessed using the Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) and the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. The Hartung-Knapp-Sidik-Jonkman random effects model was employed for reanalysis.

RESULTS: A total of 17 systematic reviews and meta-analyses encompassing 358 randomized controlled trials and 7160 participants were analyzed. tDCS demonstrated efficacy across seven distinct health conditions, including stroke, Parkinson's disease, Alzheimer's disease, cerebellar ataxia, fibromyalgia, disorders of consciousness, and migraine. Adverse effects were rarely reported, with the exception of mood changes associated with fibromyalgia. Our results indicated that tDCS significantly improved 34 distinct health outcomes related to these conditions.

CONCLUSIONS: We found that tDCS may be a promising treatment for neurological disorders, with mild and infrequent adverse effects. Further studies are warranted to validate the therapeutic potential of tDCS in the reported neurological conditions, investigate additional neurological health outcomes, and explore the underlying mechanisms of tDCS effects. The PROSPERO Registration: CRD42024589432, https://www.crd.york.ac.uk/PROSPERO/view/CRD42024589432.},
}

*Transcranial Direct Current Stimulation
Humans
*Nervous System Diseases/therapy
*Randomized Controlled Trials as Topic
Meta-Analysis as Topic
Systematic Reviews as Topic
*Outcome Assessment, Health Care/statistics & numerical data

@article {pmid42411945,
year = {2026},
author = {Nakamura, Y and Tsushio, T and Tanahashi, M and Suganami, H and Omori, T and Nishiyama, K and Aoki, H and Nagakura, N},
title = {Post Hoc Subgroup Analysis by Disease Severity in a Non-Inferiority Trial of Donepezil 27.5 mg Transdermal Formulation in Japanese Patients With Mild-to-Moderate Alzheimer Disease.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000738},
pmid = {42411945},
issn = {1546-4156},
support = {//Teikoku Seiyaku/ ; },
abstract = {BACKGROUND: The efficacy of cholinesterase inhibitors varies depending on the severity of Alzheimer disease. We examined the effects of the disease severity on the efficacy of donepezil 27.5 mg patches in Japanese patients with Alzheimer disease.

METHODS: A post hoc analysis of covariance using per-protocol set in a noninferiority study of donepezil 27.5 mg patches with donepezil hydrochloride 5 mg tablets (JapicCTI-194582) was conducted after imputation of missing data using multiple imputations.

RESULTS: No apparent imbalances in the extracted confounding factors were observed between the 2 treatment groups. The baseline value of the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale was adjusted using analysis of covariance. Least-squares mean of changes from baseline in the Alzheimer Disease Assessment Scale (Japanese version) cognitive subscale at week 24 for each group were -1.661 (-2.681 to -0.640) (donepezil patch) and 0.065 (-0.987 to 1.117) (donepezil hydrochloride tablet). The difference in the least-squares mean (95% CI) between 2 groups was -1.726 (-3.1913 to -0.2602, P=0.021).

CONCLUSIONS: A post hoc analysis of covariance using the per-protocol set suggested that donepezil patches may be more effective than donepezil tablets in slowing cognitive decline in patients with mild Alzheimer disease.},
}

@article {pmid42412004,
year = {2026},
author = {Zhang, J and Wang, Y and Lu, Z and Yang, Y and Wang, J and Zhao, L and Li, F and Miao, M and Chen, WM and Wu, SY and Sun, M},
title = {HbA1c trajectories after SGLT2 inhibitor initiation and the risk of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261462927},
doi = {10.1177/13872877261462927},
pmid = {42412004},
issn = {1875-8908},
abstract = {BackgroundType 2 diabetes mellitus (T2DM) is a major risk factor for dementia, yet the prognostic value of early dynamic glycemic changes following glucose-lowering therapy remains underinvestigated.ObjectiveTo determine whether early glycated hemoglobin (HbA1c) trajectories after initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) predict long-term dementia and mortality risks.MethodsThis retrospective new-user cohort study utilized electronic health records from the TriNetX Global Network. Adults with T2DM initiating their first SGLT2i were included. To mitigate immortal-time bias, a 1-year landmark design was applied. Patients were stratified by baseline HbA1c and classified into improved, stable, or worsened trajectories based on values 91-455 days post-initiation. Propensity-score matching was performed within strata. The primary outcome was all-cause dementia.ResultsAmong 172,050 matched patients, modest HbA1c worsening in those with Good baseline control (<7.0%) did not increase dementia risk (HR 0.93; 95% CI, 0.75-1.15). However, in patients with Fair baseline control (7.0-8.9%), worsening to Poor control significantly increased dementia (HR 1.39; 95% CI, 1.11-1.74) and mortality risks. Conversely, among those with Poor baseline control (≥9.0%), trajectory improvement conferred substantial neuroprotection, reducing the risk of dementia (HR 0.64; 95% CI, 0.51-0.79) and mortality (HR 0.71; 95% CI, 0.60-0.84). These findings provide clinically actionable evidence linking glycemic dynamics to neurodegenerative risk, particularly Alzheimer's disease and related dementias.ConclusionsDynamic HbA1c trajectories following SGLT2i initiation independently predict dementia risk. Integrating trajectory-based assessments into routine care provides an actionable, scalable biomarker to guide timely treatment intensification and mitigate diabetes-related neurocognitive decline.},
}

@article {pmid42412302,
year = {2026},
author = {Zhang, C and Ma, Y and Shi, Z and He, X and Hu, J and Chen, S and Wu, H and Tian, M and Yan, C and Xing, M and He, L},
title = {Study on the Effects and Mechanisms of Resveratrol in Improving Cognitive Impairment in Aβ1-42-Induced Alzheimer's Disease Model Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42412302},
issn = {1557-1904},
mesh = {Animals ; *Resveratrol/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; *Amyloid beta-Peptides/toxicity ; Mice ; *Peptide Fragments/toxicity ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; Disease Models, Animal ; Male ; Autophagy/drug effects ; Mice, Inbred C57BL ; *Antioxidants/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Aging is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). Targeting cellular senescence has therefore emerged as a promising therapeutic strategy. Resveratrol (RV), a natural polyphenolic compound, exhibits anti-aging properties through the regulation of autophagy and oxidative stress; however, its mechanisms in AD remain incompletely understood. In this study, we investigated the effects and underlying mechanisms of RV in an Aβ1-42-induced AD model. In vivo, RV administration significantly reduced the expression of aging-related markers and activated autophagy-associated signaling pathways. In vitro, RV treatment markedly attenuated Aβ1-42-induced cell viability loss and excessive reactive oxygen species (ROS) production. Further mechanistic analyses demonstrated that RV-induced autophagy activation was closely associated with the AMP-activated protein kinase/UNC-51-like kinase 1 (AMPK/ULK1) and silent information regulator 1/nuclear factor-kappaB (SIRT1/NF-κB) pathways. Collectively, these findings suggest that RV alleviates AD-related pathological processes by promoting autophagy and delaying cellular senescence, highlighting its potential as a therapeutic agent for age-related neurodegenerative diseases.},
}

Animals
*Resveratrol/pharmacology/therapeutic use
*Alzheimer Disease/chemically induced/drug therapy/metabolism
*Amyloid beta-Peptides/toxicity
Mice
*Peptide Fragments/toxicity
*Cognitive Dysfunction/drug therapy/chemically induced/metabolism
Disease Models, Animal
Male
Autophagy/drug effects
Mice, Inbred C57BL
*Antioxidants/pharmacology/therapeutic use
Oxidative Stress/drug effects

@article {pmid42412614,
year = {2026},
author = {Duan, W and Xing, Y and Liu, W},
title = {Protocol for generating multiplexed prime-edited monoclonal cell lines in porcine fetal fibroblasts.},
journal = {STAR protocols},
volume = {7},
number = {3},
pages = {104691},
doi = {10.1016/j.xpro.2026.104691},
pmid = {42412614},
issn = {2666-1667},
abstract = {Porcine fetal fibroblasts (PFFs) serve as standard donor cells for generating cloned pigs, and prime editing (PE) enables precise genome modification. Here, we describe a protocol for generating multiplexed prime-edited monoclonal cell lines in PFFs. We describe steps for pegRNA/ngRNA design and screening, plasmid electroporation, nocodazole treatment, puromycin selection, and monoclonal isolation and genotyping. Although demonstrated by introducing three Alzheimer's disease-associated pathogenic mutations, the pipeline can be readily adapted to multiplex PE of other endogenous loci in porcine cells. For complete details on the use and execution of this protocol, please refer to Liu et al.[1].},
}

@article {pmid42412645,
year = {2025},
author = {Hidasi, Z and Fullajtár, M},
title = {[Special aspects of the treatment of Alzheimer's disease (Anti-amyloid therapies and management of BPSD)].},
journal = {Psychiatria Hungarica : A Magyar Pszichiatriai Tarsasag tudomanyos folyoirata},
volume = {40},
number = {3-4},
pages = {274-281},
pmid = {42412645},
issn = {0237-7896},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/therapy ; *Amyloid beta-Peptides/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Immunization, Passive ; },
abstract = {Due to its diverse symptomatology, Alzheimer's disease requires a complex therapeutic approach. Among the disease-modifying pharmacotherapeutic options, significant progress has recently been made in the field of anti-amyloid antibody therapies. These are generally costly procedures in which passive immunization targets various components of the beta-amyloid cascade. The individual agents differ significantly in terms of efficacy and potential side effects/complications. Considering the questionable degree of cognitive effectiveness, and the associated risks, the exact evaluation of the practical applicability of these agents is currently not possible; long-term data analysis is needed. The symptom cluster of behavioral and psychological symptoms of dementia (BPSD) is in itself complex, encompassing a wide range of clinical phenomena. These symptoms, which frequently occur in everyday patient care and often have multifactorial origins and pathomechanisms, require a complex therapeutic approach. The therapeutic benefit of pharmacological treatments applicable to specific symptom clusters is often difficult to determine due to potential side effects; therefore, individualized treatment supplemented with non-pharmacological methods is warranted. Keywords: Alzheimer's disease; anti-amyloid therapies; behavioral and psychological symptoms of dementia (BPSD).},
}

Humans
*Alzheimer Disease/drug therapy/psychology/therapy
*Amyloid beta-Peptides/immunology
Antibodies, Monoclonal, Humanized/therapeutic use
Immunization, Passive

@article {pmid42413499,
year = {2026},
author = {Vear, A and Olsen, SA and Lange, ECH and Müller, MA and Svendsen, C and Clemmensen, C},
title = {Preventative semaglutide and tirzepatide treatment does not alter disease progression in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102906},
doi = {10.1016/j.xcrm.2026.102906},
pmid = {42413499},
issn = {2666-3791},
abstract = {There is growing evidence that long-acting mimetics of the gut-derived incretin hormones GLP-1 and GIP act as disease-modifying therapies for Alzheimer's disease (AD). Here, we temporally characterize the efficacy of the approved incretin receptor agonists semaglutide, a GLP-1R agonist, and tirzepatide, a GLP-1R/GIPR co-agonist, in preventing AD progression. In 5xFAD mice treated for 2 or 4 months, both incretin therapies lower body weight and improve glucose tolerance, yet neither compound produces measurable effects on memory or learning tasks, amyloid-β plaque deposition, or glial cell activation. In a non-amyloidogenic model, 3 days of incretin pre-treatment does not alter microglial activation or the expression of inflammatory markers following lipopolysaccharide (LPS) administration in mice. Our findings indicate that chronic semaglutide or tirzepatide treatment, even when initiated before overt pathology and delivered for a prolonged period, does not slow neuropathological progression in 5xFAD or LPS-treated mice.},
}

@article {pmid42413719,
year = {2026},
author = {Alameen, AAM and Al-Kuraishy, HM and Abdelaziz, AM and Al-Gareeb, AI and Albuhadily, AK and Batiha, GE},
title = {Targeting PARP1-dependent parthanatos in Alzheimer's disease: Mechanisms and therapeutic opportunities.},
journal = {Life sciences},
volume = {402},
number = {},
pages = {124578},
doi = {10.1016/j.lfs.2026.124578},
pmid = {42413719},
issn = {1879-0631},
abstract = {Alzheimer's disease (AD) is the predominant cause of dementia globally. This review clarifies the dual function of poly(ADP-ribose) polymerase 1 (PARP1) in AD pathogenesis, emphasizing its role in mediating parthanatos, a unique caspase-independent cell death mechanism. We analyze contemporary literature regarding PARP1 expression, parthanatos signaling, and pharmaceutical treatments in AD models. In addition, PARP1 exhibits context-dependent duality: its physiological nuclear expression in hippocampus neurons is essential for memory consolidation and decreases early in cognitive impairment, suggesting a correlative association with synaptic malfunction. In contrast, overactivity of PARP1 resulting from Aβ-induced oxidative stress and DNA damage induces neurodegeneration via multiple pathways, including NAD+/ATP exhaustion leading to metabolism collapse, creation of the AIF-MIF complex promoting parthanatos, NF-κB-induced neuroinflammation, dysregulation of mitophagy, and disruption of the neuroprotective SIRT1 signaling pathway. The overactivity contributes to a positive feedback loop, where PARP1 intensifies Aβ and tau protein accumulation while simultaneously disrupting the BBB. In preclinical models of AD, genetic knockout, pharmacologic agents such as PJ34 and MC2050, or precursors of NAD[+] such as nicotinamide and NMN attenuate Aβ deposition, normalize metabolism, and ameliorate cognitive decline. The PARP1/parthanatos pathway is at the center of the confluence of oxidative stress, DNA damage, metabolism disorder, and neuroinflammation in AD. Metformin and other PARP1 inhibitors offer intriguing treatment options. PARP1's cell-type- and intracellular location-dependent activity necessitates careful consideration of context, dose, and disease stage while developing therapies. The present understanding in this review could inform future research on PARP1 regulation in AD clinical practice.},
}

@article {pmid42403709,
year = {2026},
author = {Fontán-Baselga, T and Cañeque-Rufo, H and Rivera-Illades, E and Gramage, E and Zapico, JM and de Pascual-Teresa, B and Ramos-Álvarez, MDP and Vicente-Rodríguez, M and Herradón, G},
title = {Chronic inhibition of receptor protein tyrosine phosphatase β/ζ reduces amyloid plaque load and modulates pleiotrophin-expressing glial cells, glial-plaque interactions and genes related to amyloid beta clearance.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1839516},
pmid = {42403709},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia. Pleiotrophin (PTN) is a neurotrophic factor relevant for central nervous system repair, neuron differentiation and survival. It is upregulated in different neuroinflammatory conditions. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. In a previous study, we showed that a short treatment with the RPTPβ/ζ inhibitor MY10 reduced amyloid beta (Aβ) plaque formation and glial activation in old APP/PS1 mice. Nevertheless, these preliminary data required new studies to prove the disease-modifying potential of RPTPβ/ζ inhibition by using younger animals and a longer treatment with MY10. Thus, we have now treated for 3 months five- to seven-month-old wild type (WT) and APP/PS1 mice with MY10. This treatment decreased Aβ plaque formation and increased the number of microglial cells in the dorsal subiculum of APP/PS1 mice. In addition, MY10 reduced the number of GFAP+, not Iba1+, cells surrounding Aβ plaques. As expected, PTN expression was upregulated in the brain of APP/PS1 compared to WT mice and it was mainly found in Iba1+ and GFAP+ cells. Interestingly, treatment with MY10 significantly decreased the expression of PTN and the number of PTN-expressing Iba1+ and GFAP+ cells. MY10 induced a significant decrease of Mmp9 expression in the hippocampus of APP/PS1 mice, a key enzyme in AD progression. In summary, chronic inhibition of RPTPβ/ζ in APP/PS1 mice reduces Aβ plaque deposition, modulating glial-plaque interactions and the expression of specific genes including Ptn and its receptor.},
}

@article {pmid42403869,
year = {2026},
author = {Tuleubayeva, A},
title = {Cardiovascular Biomarkers as a Primary Care Gateway to Early Alzheimer's Disease Detection: The Case for an Integrated Screening Approach.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e110287},
pmid = {42403869},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) affects millions of Americans and represents one of the leading causes of disability and healthcare expenditure in the United States. The vast majority of patients are diagnosed at the symptomatic stage, when substantial neuronal loss has already occurred and the therapeutic window for disease-modifying treatment has closed. Recently approved disease-modifying therapies have created an urgent clinical need for pre-symptomatic patient identification. The cardiovascular risk factors most commonly managed in primary care -- hypertension, dyslipidemia, type 2 diabetes, atrial fibrillation, and chronic heart failure -- are among the most powerful modifiable antecedents of AD pathology, operating through systemic inflammation, cerebral small vessel disease, impaired glymphatic clearance, and tau hyperphosphorylation. The biomarkers used to monitor these conditions -- C-reactive protein, cardiac troponin, NT-proBNP, and homocysteine -- reflect active neurodegeneration risk processes already measured routinely in primary care. This clinical perspective proposes a three-stage integrated neuro-cardiological screening protocol linking cardiovascular biomarker assessment to plasma P-tau217 blood testing for AD confirmation. This framework addresses the implementation gap identified in recent United States primary care literature and represents a practical step toward closing the AD diagnostic gap.},
}

@article {pmid42404289,
year = {2026},
author = {Larson, ST and Susman, JL},
title = {Navigating Alzheimer's Disease in Primary Care: Practical Strategies for Diagnosis and Management.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {603347},
pmid = {42404289},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disorder that primarily affects older adults. Because the number of Americans 65 years of age and older living with AD is expected to increase and the availability of specialty physicians, such as neurologists and geriatricians, is limited, the role of primary care in diagnosing and managing patients with AD is expected to grow. Several guidelines for primary care providers are available for the evaluation, diagnosis, and treatment of patients with AD. However, there is no single concise and convenient reference tool for use in the primary care setting. In the primary care setting, clinicians are responsible for identifying patients at risk or demonstrating signs of cognitive impairment, administering cognitive tests, identifying appropriate referrals, and, in some cases, ordering blood-based biomarker testing. Although definitive testing and treatment identification may occur in the specialty care setting, in addition to serving as the hub to coordinate the multidisciplinary care team, primary care clinicians remain responsible for guiding patients and caregivers through shared decision-making regarding treatment, as well as the myriad responsibilities related to comorbidities, patient and caregiver psychological well-being, social support, and safety. This review aims to provide practical recommendations to primary care clinicians for the diagnosis, management, and long-term care of patients with AD.},
}

@article {pmid42404421,
year = {2025},
author = {Mansouri, Z and Motamedi, F and Khodagholi, F and Zahmatkesh, M},
title = {Histone Deacetylase Class IIb Inhibition Improves Amyloid-β-induced Learning and Memory Deficits in Male Rats.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {3},
pages = {583-594},
pmid = {42404421},
issn = {2008-126X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease associated with progressive impairment of cognitive function. The primary pathological features of AD include aggregation of amyloid-β (Aβ) and hyperphosphorylation of the tau protein. Histone deacetylases (HDACs) play a crucial role in the pathophysiology of neurodegenerative diseases. This study aimed to investigate the potential neuroprotective effects of HDAC6 and HDAC10 inhibition in a rodent model of AD.

METHODS: Learning and memory deficits were induced by bilateral intra-hippocampal Aβ injections in male Wistar rats. Tubacin (HDAC6 inhibitor) and bufexamac (HDAC6 and 10 inhibitors) were microinjected 30 minutes after Aβ injection. The possible molecular changes in the hippocampus following Aβ injection were also assessed by western blotting analysis of pCREB/CREB and Pp70/P70 ratios.

RESULTS: Our results revealed that bufexamac significantly recovered learning and memory impairments induced by Aβ in the Morris water maze (MWM) task. Tubacin improved memory decline without affecting learning. Bilateral intra-hippocampal injection of each of the HDAC inhibitors significantly increased the pCREB/CREB and Pp70/p70 ratios compared to the Aβ group, which was concurrent with behavioral alterations.

CONCLUSION: HDAC IIb treatment may be a promising strategy for improving learning and memory impairments in an animal model of AD, suggesting that HDAC targeting is a valuable strategy for further investigation.},
}

@article {pmid42404899,
year = {2026},
author = {Oh, SJ and Shin, OS and Hur, JY},
title = {From infection to dysfunction: viral triggers and antiviral immune factors in Alzheimer's disease pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839357},
pmid = {42404899},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/virology ; Animals ; *Virus Diseases/immunology ; Brain/immunology/virology/pathology ; Host-Pathogen Interactions/immunology ; SARS-CoV-2/immunology ; },
abstract = {Neurodegenerative diseases and neurocognitive disorders increasingly appear to share a common and underappreciated contributor: the viral-immune axis in the brain. This review presents current evidence linking neurotropic viruses and host antiviral immunity to the onset and progression of neurodegeneration and neurocognitive dysfunction. We explore how viral infections, particularly by Herpesviruses, Severe Acute Respiratory Syndrome Coronavirus 2, and Human Immunodeficiency Virus, disrupt neural homeostasis through neuroinflammation, amyloidosis, tauopathy, and autophagy dysregulation in neurodegeneration including Alzheimer's disease (AD). Simultaneously, host antiviral mechanisms, including type I interferons and interferon regulatory factors, often amplify neuronal damage when dysregulated. By examining viral and immune interactions within the neurodegenerative diseases, this review aims to broaden our understanding of the viral-immune axis in the brain and inspire novel approaches to prevention and treatment.},
}

Humans
*Alzheimer Disease/immunology/pathology/virology
Animals
*Virus Diseases/immunology
Brain/immunology/virology/pathology
Host-Pathogen Interactions/immunology
SARS-CoV-2/immunology

@article {pmid42406171,
year = {2026},
author = {Wu, H and Xia, J and Shi, Z and Zhang, C and Chen, S and Dai, L and He, L},
title = {Vorinostat Rescues Cognitive Deficits in a Neuroinflammatory Mouse Model: A Study of Sex Differences and the Underlying TLR4/NF-κB Mechanism.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42406171},
issn = {1573-6903},
mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; Male ; *Vorinostat/therapeutic use/pharmacology ; Female ; *NF-kappa B/metabolism ; Mice, Inbred C57BL ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced ; Lipopolysaccharides ; *Sex Characteristics ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Signal Transduction/drug effects ; Microglia/drug effects/metabolism ; Neuroprotective Agents/therapeutic use/pharmacology ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; },
abstract = {With the acceleration of global aging, Alzheimer's disease (AD) poses a significant public health challenge, and effective treatments are still lacking. Neuroinflammation, particularly microglia-mediated inflammation, plays a central role in AD pathogenesis, with the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway being a key regulator. The histone deacetylase inhibitor (HDACi) Vorinostat (SAHA) has shown anti-inflammatory and neuroprotective potential in preclinical studies. Given the significant sex differences in AD incidence, pathology, and treatment response, this study aimed to systematically investigate the effects of SAHA on lipopolysaccharide (LPS)-induced neuroinflammation and cognitive dysfunction, analyzing its sex-specific effects and underlying mechanisms. An LPS-induced neuroinflammation model was established in male and female C57BL/6 mice via intraperitoneal injection (1 mg/kg) for 7 consecutive days, followed by SAHA (50 mg/kg) gavage intervention for 23 days. Cognitive function was assessed using Y-maze, novel object recognition, and passive avoidance tests. Hippocampal pathology was analyzed via hematoxylin-eosin (HE) staining and Nissl staining. Western blot and quantitative PCR (qPCR) were used to detect hippocampal expression of the TLR4/TRAF6/IKKα/NF-κB pathway, inflammatory factors (IL-6, IL-1β, TNF-α, iNOS), and neuroplasticity-related proteins (BDNF, p-CREB). In vitro experiments using LPS-stimulated BV2 microglia validated SAHA's anti-inflammatory mechanisms via CCK-8, Griess assay, qPCR, and Western blot. Results showed that LPS treatment significantly activated the TLR4/TRAF6/IKKα/NF-κB pathway, upregulated hippocampal pro-inflammatory factors, caused neuronal damage, and impaired learning and memory; these effects appeared more pronounced in female mice, though this observation is exploratory and requires cautious interpretation. SAHA treatment markedly alleviated LPS-induced inflammation, neuropathology, and cognitive deficits. Notably, SAHA appeared to produce differential effects across sexes: female mice showed potentially stronger and more comprehensive improvements in cognitive recovery, downregulation of inflammatory factors, and upregulation of BDNF and p-CREB compared to males, suggesting a possible sexually dimorphic response. In vitro experiments further confirmed that SAHA significantly reduced inflammation in LPS-stimulated BV2 microglia by inhibiting the TLR4/TRAF6/IKKα/NF-κB pathway. In conclusion, this study demonstrates that SAHA exerts neuroprotective effects by inhibiting the TLR4/NF-κB pathway, thereby improving cognitive impairment, and may have a more pronounced protective effect in females. These findings suggest SAHA is a promising drug for treating neuroinflammation-induced cognitive dysfunction and highlight the importance of considering sex as a biological variable in epigenetic therapy for precision medicine.},
}

Animals
*Toll-Like Receptor 4/metabolism
Male
*Vorinostat/therapeutic use/pharmacology
Female
*NF-kappa B/metabolism
Mice, Inbred C57BL
Mice
*Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced
Lipopolysaccharides
*Sex Characteristics
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
Signal Transduction/drug effects
Microglia/drug effects/metabolism
Neuroprotective Agents/therapeutic use/pharmacology
Disease Models, Animal
Hippocampus/drug effects/metabolism
Histone Deacetylase Inhibitors/therapeutic use/pharmacology

@article {pmid42406553,
year = {2026},
author = {Wen, S and Gao, J and Wang, Z and Ma, Q and Xu, XL and Chen, J},
title = {EphB1-Mediated Transient Blood-Brain Barrier Opening Facilitates a Ferritin-Based Nanotherapeutic for Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76480},
doi = {10.1002/advs.76480},
pmid = {42406553},
issn = {2198-3844},
support = {ZKJC2203//Zhejiang Rehabilitation Medical Center/ ; ZKXK02//Zhejiang Rehabilitation Medical Center/ ; 2021C03050//Development Program of Zhejiang Province/ ; 82372109//National Natural Science Foundation of China/ ; },
abstract = {The treatment of Alzheimer's disease (AD) is severely hampered by the blood-brain barrier (BBB), which limits the delivery of therapeutic agents like donepezil (DPZ), an acetylcholinesterase inhibitor. While DPZ has multi-faceted benefits, its clinical efficacy is constrained by poor BBB penetration, requiring high doses that lead to significant side effects. To overcome this, we developed a brain-targeted nanotherapeutic utilizing apoferritin (AFn) nanoparticles loaded with DPZ (AFn-DPZ). We demonstrate that this platform, by binding to the EphB1 receptor on the blood-brain barrier, enables transient and reversible opening of the blood-brain barrier, thereby facilitating efficient and targeted drug delivery. Following intravenous administration in an AD mouse model, AFn-DPZ exhibited enhanced brain accumulation and sustained release of DPZ. This targeted delivery inhibited acetylcholinesterase activity, reduced amyloid plaque burden, alleviated neuroinflammation, attenuated oxidative damage, restored mitochondrial function, and upregulated the expression of brain-derived neurotrophic factor (BDNF). Consequently, AFn-DPZ treatment significantly improved cognitive performance compared to free DPZ. Our findings establish EphB1-mediated facilitation of BBB traversal as a promising strategy for enhancing nanotherapeutic delivery to the brain, offering a potent approach to address the complex pathology of AD.},
}

@article {pmid42406649,
year = {2026},
author = {Zawadzki, S and Okła, E and Michlewska, S and Bednarek, R and Ortega López, P and de la Mata, FJ and Jansons, J and Skrastina, D and Kreišmane, M and Piļipenko, V and Jansone, B and Ionov, M and Bryszewska, M and Miłowska, K},
title = {Tiered Evaluation of Carbosilane Dendrimer-siRNA Nanoplatform from Single-Cell Biocompatibility to Blood-Brain Barrier Model Dynamics and Murine Alzheimer Model Behavior Assessment.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c06099},
pmid = {42406649},
issn = {1944-8252},
abstract = {Blood-brain barrier (BBB) transport remains a primary constraint on achieving predictable central nervous system exposure for Alzheimer's disease (AD) therapeutics, motivating the evaluation of delivery platforms with barrier-resolved and functionally relevant end points. We assessed a carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex using a tiered, upstream strategy spanning cell internalization, DNA damage screening, BBB model integrity and permeability, and in vivo AD-relevant murine model learning. At the cellular level, the dendrimer enhanced intracellular siRNA-associated signal with predominantly cytoplasmic localization, and siRNA complexation attenuated genotoxicity relative to the noncomplexed carrier. In a BBB triculture model, barrier function was preserved without sustained transendothelial electrical resistance (TEER) loss, and complementary tracer flux readouts showed time- and formulation-dependent, nonmonotonic changes, including TEER-permeability decoupling consistent with nonuniform perturbation and time-dependent changes in barrier-associated paracellular responses. In APOE4 knock-in mice, dendriplex treatment increased platform-zone crossings in the Morris Water Maze probe trial, whereas target-quadrant time showed only a modest, nonsignificant trend. Collectively, these integrated results indicate that siRNA complexation improves the BBB-relevant safety-performance balance of G3Si PEG6000 and supports further studies that directly link brain exposure and target engagement to cognitive outcomes.},
}

@article {pmid42410071,
year = {2026},
author = {Suo, X and Wan, P and Yu, J and Zhu, X and Tian, C and Li, S and Sun, G and Liu, H and Liu, S and Geng, M and Tian, J and Yang, W and Zhang, Y},
title = {The Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42410071},
issn = {1573-6903},
support = {2024CXPT029, 2025CXPT011//Key R&D Program of Shandong Province, China/ ; SYS202205//Shandong Laboratory Program/ ; ZR2024QH615//Shandong Provincial Natural Science Foundation/ ; },
mesh = {Animals ; Lipopolysaccharides/toxicity ; Mice, Transgenic ; *tau Proteins/genetics/metabolism ; Female ; *Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention & control ; Mice ; Microglia/drug effects/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Alzheimer Disease/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; Mice, Inbred C57BL ; },
abstract = {Neuroinflammation and tau pathology are central drivers of Alzheimer's disease (AD) progression, necessitating multi-target therapeutic strategies. Here, we evaluated the efficacy and mechanisms of 0242, a novel small-molecule derivative optimized from the berberine scaffold. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, 0242 treatment significantly inhibited cell activation and nitric oxide release without cytotoxicity, while downregulating the mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α. Transcriptomic profiling revealed that 0242 modulated LPS-induced inflammatory gene signatures by enriched core signaling cascades, including NF-κB, TLR, and JAK-STAT and upregulating cytoprotective genes such as ceruloplasmin (Cp) and Bcl2a1b. In vivo, oral administration of 0242 attenuated hippocampal astrocyte and microglial activation in an LPS-induced acute neuroinflammatory mouse model. Furthermore, in female P301S tau transgenic mice, 0242 treatment significantly improved spontaneous locomotor activity and recognition memory. Histological and biochemical analyses confirmed that 0242 suppressed hippocampal glial activation and reduced total tau protein levels in the prefrontal cortex. Collectively, these findings suggest that 0242 may exert potent anti-neuroinflammatory effects by modulating multiple immune signaling cascades and uniquely alleviates tau pathology in AD.},
}

Animals
Lipopolysaccharides/toxicity
Mice, Transgenic
*tau Proteins/genetics/metabolism
Female
*Neuroinflammatory Diseases/chemically induced/metabolism/drug therapy/prevention & control
Mice
Microglia/drug effects/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Alzheimer Disease/drug therapy/metabolism
Hippocampus/drug effects/metabolism
Mice, Inbred C57BL

@article {pmid42410083,
year = {2026},
author = {Costello, H and Reeves, S and Glue, P and Young, AH and Howard, R},
title = {Depression in neurodegenerative disease: neurobiological mechanisms and emerging treatments.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42410083},
issn = {1476-5578},
abstract = {Depression is one of the most common and disabling neuropsychiatric complications of neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), depressive syndromes affect more than one-third of patients and are associated with accelerated cognitive decline, reduced quality of life, and increased healthcare utilisation. Despite this burden, current antidepressant treatments show little or no efficacy in these populations, suggesting that depression arising in the context of neurodegeneration may reflect distinct underlying neurobiological mechanisms. Emerging evidence from molecular imaging, neuropathology, and cognitive neuroscience indicates disease-specific disruption of monoaminergic, glutamatergic, inflammatory, and reward-related circuits in AD and PD. These alterations may undermine the mechanisms of action of standard antidepressants and contribute to treatment resistance. Yet patients with cognitive impairment are routinely excluded from antidepressant trials, and few high-quality studies have evaluated novel therapies in neurodegenerative disease. In this narrative review, we synthesise current evidence on the neurobiological mechanisms underpinning depression in AD and PD and critically evaluate emerging pharmacological and neuromodulatory therapies targeting glutamatergic, serotonergic, dopaminergic, immune, and circuit-level dysfunction. Here, we highlight that depression in neurodegenerative disease offers a unique and underutilised model for mechanistically guided antidepressant development. We identify how interventions including glutamate modulators, dopaminergic agents, kappa opioid antagonists, immune-modulating therapies, and next-generation brain stimulation approaches may offer therapeutic promise. By aligning treatment development with disease-specific circuit and molecular pathology, this framework may improve outcomes for this neglected population while advancing precision psychiatry more broadly.},
}

@article {pmid42410183,
year = {2026},
author = {de Oliveira Portugal Couto, C and Hass das Eiras, ML and Juliao de Morais, JL and Leal Cordeiro Júnior, CW and Forlenza, OV and de Jesus Rodrigues de Paula, V},
title = {Chronic Lithium Exposure Reshapes PI3K-mTOR-linked Proteostatic Networks in the Hippocampus of an Alzheimer's Disease Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42410183},
issn = {1559-1182},
mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Phosphatidylinositol 3-Kinases/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *TOR Serine-Threonine Kinases/metabolism ; *Lithium/pharmacology/administration & dosage/therapeutic use ; Signal Transduction/drug effects ; Protein Interaction Maps/drug effects ; Proteomics ; Mice ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β deposition, tau pathology, and alterations in signaling pathways involved in neuronal survival and protein homeostasis. Lithium has been suggested as a potential neuroprotective treatment, but the molecular mechanisms associated with its long-term effects are still not fully understood. In this study, we investigated the effects of chronic lithium treatment on hippocampal proteins associated with PI3K-related signaling in triple-transgenic Alzheimer's disease (3xTg-AD) mice. Wild-type and transgenic animals received either a lower or higher lithium dose for eight months. Hippocampal samples were analyzed by LC-MS/MS proteomics followed by protein interaction and functional enrichment analyses. From a total of 7768 identified proteins, bioinformatic analyses identified 157 proteins shared between APP-, MAPT-, and PI3K-associated datasets. Further network analyses identified 18 proteins related to PI3K signaling, including seven proteins shared among all three datasets: FKBP1A, HSPA1B, HSPA8, RAS-related proteins, RPL13, RPL19, and RPL24. These proteins are associated with protein folding, translation regulation, cellular stress responses, and signaling pathways. Chronic lithium treatment was associated with changes in the expression of these proteins in both wild-type and transgenic animals. The observed effects differed between the two lithium concentrations tested and did not follow a simple linear pattern. Our findings suggest that long-term lithium exposure is associated with changes in molecular networks related to proteostasis and translational regulation in the hippocampus. Although additional studies are needed to better understand the mechanisms involved, these results provide a proteomic framework for investigating lithium-sensitive pathways that may be relevant to Alzheimer's disease.},
}

Animals
*Hippocampus/metabolism/drug effects/pathology
*Alzheimer Disease/metabolism/drug therapy/pathology
*Phosphatidylinositol 3-Kinases/metabolism
Mice, Transgenic
Disease Models, Animal
*TOR Serine-Threonine Kinases/metabolism
*Lithium/pharmacology/administration & dosage/therapeutic use
Signal Transduction/drug effects
Protein Interaction Maps/drug effects
Proteomics
Mice

@article {pmid42395049,
year = {2026},
author = {Hofmann, A and Perneczky, R},
title = {Obstacles and solutions for implementing amyloid-targeting treatments in Europe.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70367},
pmid = {42395049},
issn = {2352-8729},
abstract = {Recent approvals of disease-modifying therapies by the European Medicines Agency mark a historic shift in the treatment landscape of Alzheimer's disease (AD) within the European Union that will challenge national health-care systems and require major adaptations and modernization. This Perspective article provides an overview of the major obstacles in Europe concerning successful implementation of amyloid-targeting treatments and offers potential solutions to overcome them. Major hurdles include a lack of recognition regarding the critical importance of an early, biomarker-based AD diagnosis; low acceptance of blood tests and digital cognitive screening tools; insufficient investment in magnetic resonance imaging capacities; and a fragmented infrastructure for clinical registries. We call on European clinicians, research institutions, and policy makers for a bold and coordinated action to urgently modernize diagnostic pathways and monitoring infrastructure to deliver novel AD treatments in a timely, safe, and equitable manner to all patients who may benefit.},
}

@article {pmid42395345,
year = {2026},
author = {Zhao, B and Zhou, R and Liu, P and Li, Q and Yan, Y and Du, J and Zhao, K and Liu, J and Wang, J and Qu, Q},
title = {FLOT1 and EEF1D: ac4C-related genes bridging Alzheimer's disease and sleep deprivation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1825164},
pmid = {42395345},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) and sleep deprivation (SD), two common conditions in the elderly, share complex molecular connections and may mutually influence each other's pathogenesis. Current drugs only relieve symptoms with limited efficacy, making it urgent to explore the shared pathological mechanisms and potential intervention targets of the two conditions. This study used bioinformatics: first screening AD-related genes associated with SD and N4-acetylcytidine (ac4C) from relevant data; then identifying key genes via Mendelian randomization (MR) analysis and machine learning; finally screening AD-related key cells with single-cell RNA sequencing (scRNA-seq) data, to provide a basis for revealing the molecular and cellular regulatory mechanisms of AD-SD comorbidity.

METHODS: This study integrated bulk RNA sequencing (RNA-Seq) and scRNA-seq data from the Gene Expression Omnibus (GEO) database to identify AD-related key genes associated with SD and ac4C. Machine learning algorithms, including MR, were applied to screen these key genes. Additionally, gene set enrichment analysis (GSEA) was conducted to explore the pathways associated with the key genes, while ssGSEA was used to assess differences in immune cell infiltration. For the scRNA-seq data, key cells involved in AD pathology were further identified. Subsequently, the differential expression of the two key genes was validated using peripheral blood samples collected from AD and SD patients.

RESULTS: Through MR analysis, machine learning algorithms, and other analytical approaches, FLOT1 and EEF1D were identified as key genes. GSEA revealed that these key genes were enriched in multiple pathways, including the lysosome pathway, chemokine signaling pathway, and leukocyte transendothelial migration. Immune cell infiltration analysis suggested that myeloid-derived suppressor cells (MDSCs) might serve as key immune cells. Additionally, scRNA-seq analysis identified microglia, CD4 + T cells, CD8 + T cells, and natural killer (NK) cells as key cell types involved in AD pathogenesis. Critically, these key genes were successfully validated in peripheral blood samples from AD and SD patients, aligning with the above analysis.

CONCLUSION: Overall, FLOT1 and EEF1D were identified as key genes associated with SD and ac4C in AD. This finding provided new grounds for the clinical diagnosis and treatment of AD.},
}

@article {pmid42395350,
year = {2026},
author = {Van Skike, CE and Hernandez, SF and Hussong, SA and Miller, LR and Makhlouf, H and Muppala, AC and DeRosa, N and Jahrling, JB and Dineley, KT and Galvan, V},
title = {mTOR drives cerebrovascular dysfunction and blood-brain barrier breakdown in a model of Alzheimer's disease with cerebral amyloid angiopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.23.733858},
pmid = {42395350},
issn = {2692-8205},
abstract = {Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid β fibrils (Aβ) within walls of the cerebrovasculature and contributes to intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in patients with Alzheimer's disease (AD) and in non-pathological aging. Previous studies have shown that mTOR drives cerebrovascular dysfunction and cognitive impairment observed in AD, vascular cognitive impairment, and normative aging. However, the mechanisms by which mTOR contributes to CAA are unknown. Here, we show that mTOR drives the accumulation of fibrillar vascular Aβ lesions in the Tg2576 Model of AD with CAA (using equal numbers of female and male mice), which directly impair endothelium-dependent cerebrovascular reactivity. Additionally, we found that blood-brain barrier (BBB) breakdown and remodeling of tight junction proteins, dependent on mTOR, are associated with increased cerebral microhemorrhages. Finally, we show that mTOR contributes to neurovascular uncoupling in Tg2576 AD mice through nNOS dysfunction and inhibition of non-nitric oxide synthase-dependent contributions to neurovascular coupling (NVC). Contextual memory impairments were ameliorated by the mTOR inhibitor rapamycin. Improvements in memory were associated with reduced cerebrovascular Aβ fibril accumulation, enhanced endothelium-dependent vasodilation, reduced fibrillar Aβ load, restoration of BBB integrity, attenuation of intracerebral microhemorrhage, and restoration of NVC. These data indicate that mTOR drives vascular accumulation of fibrillar Aβ, including those associated with brain vasculature, and mediates cerebrovascular dysfunction in a model of AD with CAA. Thus, mTOR inhibitors represent a promising treatment option for patients with CAA and AD.},
}

@article {pmid42395404,
year = {2026},
author = {Giorgio, J and Blazhenets, G and Landau, SM and Pezzoli, S and Yokoyama, JS and Soleimani-Meigooni, DN and Carrillo, MC and Grinberg, LT and Seeley, WW and Spina, S and Nudelman, KN and Apostolova, LG and Dickerson, BC and Jagust, WJ and Rabinovici, GD and Joie, R and , and , },
title = {Characterisation of Posterior Predominant Amyloid PET Binding Across Multiple Cohorts.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.17.733031},
pmid = {42395404},
issn = {2692-8205},
abstract = {The standard approach to quantify amyloid (Aβ) PET averages uptake within a single cortical mask that assumes no clinically relevant spatial heterogeneity in uptake patterns. Here, in a sample of 12,379 clinically impaired participants taken from four phenotypically diverse cohorts we use data-driven approaches to discover heterogeneous patterns of Aβ-PET binding, uncovering a reproducible and clinically relevant pattern of posterior predominant Aβ-PET binding. In particular, Aβ-PET positive participants who have posterior predominant binding are less likely to be APOE -ε4 carriers, more severely impaired, have thinner cortex in posterior regions, and greater posterior tau PET burden. Furthermore, in a subsample of participants with neuropathological assessment, participants with posterior predominant Aβ binding have a higher likelihood of having cerebral amyloid angiopathy at autopsy. These findings suggest that Aβ-PET accumulates along two orthogonal axes with biological and clinical relevance, indicating that the standard approach to assess Aβ-PET is insufficient to capture meaningful signal from Aβ-PET imaging. This work has implications for the diagnosis and treatment of Alzheimer's disease and extends our understanding of the mechanisms governing variable Aβ-PET distribution and its downstream effects.},
}

@article {pmid42395537,
year = {2024},
author = {Wang, R and Maloney, B and Nho, K and Beck, J and Counts, SE and Lahiri, DK},
title = {Human microRNA-153-3p targets specific neuronal genes and is associated with the risk of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.09.07.611728},
pmid = {42395537},
issn = {2692-8205},
abstract = {Alzheimers disease (AD) is a progressive degenerative disease characterized by a significant loss of neurons and synapses in cognitive brain regions and is the leading cause of dementia worldwide. AD pathology comprises extracellular amyloid plaques and intracellular neurofibrillary tangles. However, the triggers of this pathology are still poorly understood. Repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF), a transcription repressor of neuronal genes, is dysregulated during AD pathogenesis. How REST is dysregulated is still poorly understood, especially at the post-transcriptional level. MicroRNAs (miRNAs), a group of short non-coding RNAs, typically regulate protein expression by interacting with target mRNA transcript 3-untranslated region (UTR) and play essential roles in AD pathogenesis. Herein, we demonstrate that miR-153-3p reduces REST 3-UTR activities, mRNA, and protein levels in human cell lines, along with downregulating amyloid β precursor protein (APP) and α-synuclein (SNCA). We determine by mutational analyses that miR-153-3p interacts with specific targets via the seed sequence present within the respective mRNA 3-UTR. We show that miR-153-3p treatment alters the expression of these specific proteins in human neuronally differentiated cells and human induced pluripotent stem cells and that miR-153-3p is itself dysregulated in AD. We further find that single nucleotide polymorphisms (SNPs) within 5kb of the MIR153-1 and MIR153-2 genes are associated with AD-related endophenotypes. Elevation of miR-153-3p is associated with reduced AD probability, while elevated REST may associate with a greater AD probability. Our work suggests that a supplement of miR-153-3p would reduce levels of toxic protein aggregates by reducing APP, SNCA, and REST expression, all pointing towards a therapeutic and biomarker potential of miR-153-3p in AD and related dementias.},
}

@article {pmid42396326,
year = {2026},
author = {Ferreira-Atuesta, C and Schubert, KM and Noain, D and Draganski, B and Galovic, M and , },
title = {Association of antiseizure medication with lower amyloid and tau burden.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.22.26356204},
pmid = {42396326},
abstract = {Network hyperexcitability is increasingly implicated in prodromal Alzheimer's disease and may be suppressed by antiseizure medications (ASMs). ASMs are widely prescribed to older adults, yet whether their use relates to Alzheimer's-disease biomarkers at the population level is unknown. In 52,537 participants in the National Alzheimer's Coordinating Center (NACC) study, we compared cerebrospinal-fluid biomarkers, amyloid and tau positron emission tomography (PET) between ASM users and non-users using inverse-probability-of-treatment weighting with gradient-boosted propensity scores. ASM users showed directionally lower amyloid across multiple brain regions, amplifying markedly in APOE ε4 carriers (Centiloid β = -25.7, p = 0.007). All three temporal tau-PET composites were significantly lower in users (META-temporal β = -0.05, p = 0.01). The amyloid finding replicated independently in the the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset (Centiloid β = -8.6, p = 0.01), whereas four comparator drug classes showed no amyloid signal. These convergent observational findings provide a quantitative framework for evaluating ASMs as candidate disease-modifying agents in Alzheimer's disease.},
}

@article {pmid42398193,
year = {2026},
author = {Saumur, TM and Ashraf, H and Mathers, KE and Wagner, B},
title = {Pharmacotherapy for Alzheimer's Disease and Dementias in Long-Term Care: A Real-World EHR Study.},
journal = {Journal of the American Medical Directors Association},
volume = {27},
number = {9},
pages = {106293},
doi = {10.1016/j.jamda.2026.106293},
pmid = {42398193},
issn = {1538-9375},
abstract = {OBJECTIVES: To characterize contemporary pharmacologic medication order patterns for Alzheimer's disease (AD) and related dementias (ADRD) among US long-term care (LTC) residents and to examine facility- and resident-level factors associated with treatment.

DESIGN: Retrospective and observational study.

SETTING AND PARTICIPANTS: Electronic health record data from 1,675,873 LTC residents in the PointClickCare Life Sciences clinical database included 295,946 with a documented ADRD diagnosis in skilled nursing facilities in the United States who remained in facility at the end of the study window (January-April 2025).

METHODS: Residents were classified as treated/untreated based on the presence of ≥1 ADRD medication order as outlined by the Alzheimer's Association. Analyses incorporated demographics, comorbidities, medication burden, and facility characteristics. Multivariate logistic regression estimated the odds of having an ADRD medication order.

RESULTS: Overall, 82.0% of residents with ADRD had ≥1 order for ADRD medication. Treatment was most common among residents with Lewy body dementia (91.1%) and early onset AD (90.3%) and least frequent among Asian (72.3%), Native Hawaiian, or Other Pacific Islander (74.6%) and short-stay residents (75.6%). Treated residents exhibited a higher medication burden (mean, 8.6 vs 6.3). Diagnoses for other chronic conditions as well as specific ADRD subtypes strongly impacted probability of treatment; diabetes was associated with lower odds of treatment, whereas ADRD subtypes strongly predicted treatment.

CONCLUSIONS AND IMPLICATIONS: Approximately one-fifth of residents with ADRD did not have an ADRD medication order, and treatment varied significantly by nonclinical predictors. These findings underscore the need to investigate and understand possible treatment disparities, optimize polypharmacy management, and discover new ADRD treatments, and develop safer and more effective ADRD therapies.},
}

@article {pmid42398685,
year = {2026},
author = {Tang, Y and Huang, L and Li, W and Gao, T and Shi, N and Zhu, Y and Wang, Y and Nan, J and Zhu, Y and Li, J and Ma, Y},
title = {Efficacy of Non-Invasive Brain Stimulation in Alzheimer's Disease: An Umbrella Review of Meta-Analyses.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106844},
doi = {10.1016/j.neubiorev.2026.106844},
pmid = {42398685},
issn = {1873-7528},
abstract = {This umbrella review integrates systematic reviews and meta-analyses to evaluate the efficacy of non-invasive brain stimulation (NIBS) in Alzheimer's disease (AD). We searched seven databases from inception to 20 June 2025 for relevant literature. Effect sizes and 95% confidence intervals were extracted using a structured approach and visualized through effect size heatmaps and evidence mapping. Methodological quality and evidence certainty were assessed using AMSTAR 2 and GRADE, respectively. A total of 42 publications, encompassing 130 primary studies and 5,771 patients, were included. NIBS yielded significant immediate improvements in global cognition, daily living, neuropsychiatric symptoms, memory, language, executive function, global impression, visuospatial function, and cholinergic transmission. Among 119 outcome associations, 57.1% were statistically significant (p < 0.05). Long-term benefits were sustained only in global cognition. Moreover, these techniques exhibited modality-specific effects on cognitive and clinical outcomes. Subgroup analysis identified repetitive transcranial magnetic stimulation (rTMS) as the most effective technique, supported by 16 moderate- to high-quality associations. Transcranial direct current stimulation (tDCS) showed inconsistent results with only three moderate-quality associations, while transcranial alternating current stimulation (tACS) demonstrated potential but limited evidence. Intermittent theta burst stimulation (iTBS) showed no significant cognitive benefits in the limited available evidence. Available safety evidence, though limited, suggests generally mild and transient adverse effects. NIBS, particularly rTMS, shows therapeutic potential for AD, though this is based on preliminary evidence. Future multicenter long-term studies and standardized protocols are needed to facilitate the precise application of NIBS in AD treatment.},
}

@article {pmid42399403,
year = {2026},
author = {Endrizzi, W and Ragni, F and Bovo, S and Chandra, A and Moroni, M and Jurman, G and Osmani, V},
title = {The landscape of artificial intelligence in neurodegenerative diseases: a systematic review.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01669-5},
pmid = {42399403},
issn = {2730-664X},
abstract = {BACKGROUND: The rising global burden of neurodegenerative diseases underscores an urgent need for advanced research in diagnosis, prognosis, and treatment. Artificial Intelligence (AI) methods, particularly when applied to multimodal data, offer a powerful tool to address these challenges. However, a comprehensive overview and critique of the current landscape of AI methods is lacking.

METHODS: 4,685 records of peer-reviewed, primary research articles were screened and 1,956 articles reviewed in full text, yielding 1,186 included studies. For each included study, clinical objectives, disease focus, data modalities, modelling approach, evaluation strategy, and reporting practices were extracted.

RESULTS: Fewer than 5% of studies integrated pharmacological treatments into their predictive models, limiting the extent to which models can directly inform clinical decision-making. Neuroimaging was the predominant input modality, while integration of other clinically relevant data types was relatively rare. Reproducibility rates remain critically low at 35%, and external validation practices fail to use geographically and demographically diverse datasets.

CONCLUSIONS: Overall, AI research in neurodegenerative diseases suffers from significant limitations in reproducibility, data inclusivity, and clinical translatability. We provide a set of recommendations that can be adopted to address these issues and improve reliability and downstream clinical utility.},
}

@article {pmid42401549,
year = {2026},
author = {Liu, C and Zhang, T and E, ED and Xu, TY and Yang, FR and Li, JW and Shang, Q and Zhang, ZY and Shen, HW and Zhang, XQ},
title = {Maraviroc attenuates inflammation-exacerbated cognitive and amyloid pathology in an early-stage Alzheimer's disease mouse model.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04215-y},
pmid = {42401549},
issn = {2158-3188},
support = {32201322//National Natural Science Foundation of China (National Science Foundation of China)/ ; LY24H090001//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline, and increasing evidence indicates that systemic inflammation can accelerate disease progression. Maraviroc, a CCR5 antagonist approved for the treatment of human immunodeficiency virus (HIV) infection, has shown neuroprotective effects in several neurological contexts, but its role in AD-related pathology remains unclear. In this study, cognitive performance was assessed in 5 × FAD mice using the Y-maze, novel object recognition, novel location recognition, and social discrimination tests. Amyloid-related changes were evaluated by hippocampal APP/Aβ immunoblotting and plaque staining using 6E10 and Thioflavin S. Glial responses were examined by IBA1 and GFAP immunostaining, and inflammatory cytokines were quantified by ELISA. We found that 5 × FAD mice exhibited age-dependent cognitive impairments, with detectable deficits emerging at 3 months of age. Systemic administration of lipopolysaccharide (LPS) further exacerbated cognitive dysfunction, amyloid-related alterations, and neuroinflammatory responses in young 5 × FAD mice. Maraviroc treatment attenuated LPS-associated cognitive impairments, reduced amyloid-related measures, and dampened pro-inflammatory cytokine responses, with a trend toward reduced microglial cell density. Collectively, these findings demonstrate that systemic inflammation accelerates Alzheimer's-like pathology and cognitive decline, and suggest that pharmacological modulation of neuroinflammatory signaling by maraviroc may mitigate inflammation-driven disease exacerbation at early stages.Schematic diagram illustrating the effects of maraviroc on LPS-induced cognitive deficits in 3-month-old 5 × FAD mice. In this model, maraviroc is associated with modulation of glial inflammatory responses, reduced pro-inflammatory cytokine levels, and alleviation of amyloid pathology in the hippocampus, which together coincide with improved cognitive performance. Figure created with BioRender.com.},
}

@article {pmid42402307,
year = {2026},
author = {Chen, Z and Yang, K and Lin, F and Tang, W and Shi, Y and Zhou, S and Liu, J and You, Y},
title = {White matter abnormalities in Alzheimer's disease: Implications for pathophysiology, diagnosis, and treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103229},
doi = {10.1016/j.arr.2026.103229},
pmid = {42402307},
issn = {1872-9649},
abstract = {White matter (WM) abnormalities have emerged as a critical element in Alzheimer's disease (AD) pathogenesis, shifting from their former status as a passive consequence to an active contributor to disease progression. Notably, microstructural WM alterations, detectable early via advanced neuroimaging techniques such as diffusion tensor imaging, frequently precede overt gray matter atrophy and cognitive decline, highlighting their potential as early contributors to AD pathogenesis. The origins of WM pathology are multifactorial, involving a complex interplay among β-amyloid (Aβ) and tau aggregation, energy dysmetabolism, neuroinflammation, vascular dysfunction, and cellular senescence. Importantly, we emphasize a paradigm-shifting perspective: WM degeneration acts not merely as a downstream outcome but as a key driver of AD pathogenesis, capable of accelerating protein aggregation, amplifying neuroinflammation, and compromising neural plasticity. Given its early manifestation and close association with symptom onset, WM integrity has emerged as a sensitive and reliable biomarker for early AD detection and progression monitoring. Moving beyond diagnostics, the growing understanding of WM pathophysiology has unveiled a new frontier of therapeutic interventions aimed at myelin regeneration and WM protection. Despite persisting translational challenges, targeting WM integrity represents a pivotal avenue for developing disease-modifying therapies capable of slowing disease progression and improving clinical outcomes in patients with AD.},
}

@article {pmid42402880,
year = {2026},
author = {, },
title = {[Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {25},
pages = {2568-2578},
doi = {10.3760/cma.j.cn112137-20260202-00363},
pmid = {42402880},
issn = {0376-2491},
support = {2023YFC3605400//National Key Research and Development Program of China/ ; 82588301//Natural Science Foundation of China/ ; 2024GGXM003//Joint Project of the Chongqing Science and Technology Bureau and the Health Commission/ ; },
mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biomarkers/blood ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; },
abstract = {Alzheimer's disease (AD) is a major health threat to the elderly. With the clinical application of disease-modifying therapeutic drugs, early and accurate diagnosis of AD has become increasingly essential. Given the ease of collection, blood biomarker detection has emerged as a crucial method for early screening, clinical diagnosis, and disease monitoring of AD. In recent years, substantial progress has been achieved in the research of AD blood biomarkers, and some indicators have been introduced into clinical practice. However, the detection of AD blood biomarkers, such as β-amyloid protein and phosphorylated tau protein, are highly susceptible to pre-analysis factors, which reduces the reliability of their clinical application and restricts the comparability among different blood biomarker studies. Currently, in China, there is a growing trend in the scientific research, testing product development, and clinical application of AD blood biomarkers. Therefore, it is necessary to standardize the AD blood biomarker detection in China. Based on this background, Cognitive Impairment Working Group of the National Medical Quality Control Center for Neurological Diseases established the "Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)". This standard is developed in line with international recommendations, incorporating the practical experience of blood biomarker research in China and taking into consideration both clinical and research needs. It formulates a standardized operating procedure for the pre-treatment of blood samples, providing a quality control reference for the research and clinical application of AD blood biomarkers in China.},
}

*Alzheimer Disease/blood/diagnosis
Humans
*Biomarkers/blood
Amyloid beta-Peptides/blood
tau Proteins/blood

@article {pmid42394935,
year = {2026},
author = {Leone, L and Kiernan, TJ and Kuwabara, S and Barnett, M and Devenney, E and Ahmed, RM and Lin, CS},
title = {A convergence of global epidemics: diabetes as a modulator of neurodegenerative and neuro-inflammatory disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1824840},
pmid = {42394935},
issn = {1664-2295},
abstract = {Diabetes mellitus (DM) and neurological disorders are rapidly converging global health burdens, driven by population ageing, the growing prevalence of metabolic syndrome, and limited early detection and disease-modifying therapies for many neurological syndromes. Beyond its established role in diabetes-related peripheral neuropathy, DM is increasingly implicated as a modifier of risk, phenotype, and prognosis across a wide range of central and peripheral nervous system diseases. In this narrative review, we synthesize current epidemiological, clinical, genetic, and mechanistic evidence examining the relationship between DM and 10 clinically important neurological disorders: Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multiple sclerosis (MS), myasthenia gravis (MG), and neuromyelitis optica spectrum disorder (NMOSD). Across these conditions, DM acts as a context-dependent disease modifier, increasing risk in some disorders, appearing protective or delaying onset in others, and influencing disease phenotype, progression, and treatment response. We highlight potential areas of mechanistic convergence, such as insulin resistance, inflammation, disrupted energy homeostasis, and genetic predisposition, alongside important divergences shaped by disease-specific pathology. We also discuss the clinical and translational implications of this interface, including diagnostic challenges, opportunities for improved risk stratification, and growing interest in repurposing antidiabetic therapies, particularly metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, for neurological benefit. As the global burden of diabetes and neurological disease escalates, it is crucial to better understand the interplay between metabolic dysfunction, neurodegeneration, and neuro-immune pathways. The integration of insights across diseases may inform prevention strategies and support the development of therapeutic interventions at the metabolic-neurological interface.},
}

@article {pmid42394931,
year = {2026},
author = {Jeon, YH and Kim, JA and Kang, DY and Lee, S and Choi, NK and Park, JY},
title = {Ginkgo biloba extract for dizziness-related symptoms in central neurological disorders: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860538},
pmid = {42394931},
issn = {1664-2295},
abstract = {BACKGROUND AND PURPOSE: Dizziness associated with central neurological disorders-broadly defined as dizziness or vertigo attributable to central nervous system pathology affecting central vestibular processing-is a clinically challenging and heterogeneous condition with limited treatment options. Ginkgo biloba extract-through its microcirculatory, neuroprotective, and anti-inflammatory mechanisms-represents a biologically plausible intervention. However, its efficacy in this setting has not been comprehensively established. We evaluated the efficacy and safety of Ginkgo biloba extract through a systematic review and meta-analysis of randomized controlled trials (RCTs).

METHODS: Nine international and Korean databases were searched from January 1974 through November 2025. Studies were eligible if they were RCTs enrolling adults aged 18 years or older with cerebrovascular disease, neurodegenerative disease, or central vestibular dysfunction who had dizziness, vertigo, or balance-related symptoms or relevant outcome assessments. Cochrane RoB 2.0 tool and certainty of evidence was rated using the Assessment, Development and Evaluations (GRADE) approach. Prespecified subgroup analyses by underlying etiology and intervention type, together with leave-one-out sensitivity analyses, were performed to explore heterogeneity.

RESULTS: Nine RCTs (N = 2,394) were included; participants were predominantly drawn from dementia populations (71.6%), with smaller contributions from cerebral arteriosclerosis (23.0%) and vertebrobasilar or posterior circulation disorders (5.4%). Ginkgo biloba significantly reduced dizziness/vertigo severity on the 11-point box scale (MD - 0.76, 95% CI - 1.35 to -0.18; p = 0.01) and VAS (SMD - 0.38, 95% CI - 0.58 to -0.19; p = 0.0001). Moderate-certainty evidence suggested improvements in functional outcomes and quality of life, including the Alzheimer's Disease Activities of Daily Living International Scale (MD = -0.17, 95% CI: -0.22 to -0.13) and the Dementia Quality of Life - Proxy (MD = 2.00, 95% CI: 0.85 to 3.15). The intervention was generally well tolerated, with significantly lower risks of angina pectoris (OR 0.51, 95% CI 0.31 to 0.85) and tinnitus (OR 0.37, 95% CI 0.22 to 0.63) and no significant increase in other adverse events.

CONCLUSION: Ginkgo biloba extract may reduce dizziness severity and improve daily functioning in patients with central neurological disorders accompanied by dizziness or vertigo, with a favorable safety profile. However, given the small number of eligible trials, substantial clinical and statistical heterogeneity, and the predominance of dementia-derived data, these findings should be interpreted with caution. Well-designed RCTs in clearly defined central vestibular populations, ideally confirmed by neuroimaging or vestibular testing, are needed to confirm these results.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251229692, PROSPERO: CRD420251229692.},
}

@article {pmid42390710,
year = {2026},
author = {Medeiros, EB and de Oliveira Monteiro, I and Kluwe-Schiavon, B and Possamai, OL and Fenilli, GP and Keller, GS and Lidio, AV and Casagrande, DD and Souza, CSM and de Bem Silveira, G and de Almeida, RCS and Vicente, HB and Magenis, ML and Luiz, GP and Damiani, AP and de Andrade, VM and Budni, J},
title = {Effect of Probiotic Supplementation in Older Individuals with Mild Cognitive Impairment and Alzheimer's Disease: A Randomized, Placebo-Controlled, Triple-Blind Clinical Trial.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42390710},
issn = {1867-1314},
abstract = {Alzheimer's disease (AD) is the most common type of dementia in older adults and often precedes mild cognitive impairment (MCI). These conditions are associated with biological alterations involving chronic inflammation, neuronal dysfunction, and genomic instability. In parallel, growing evidence has suggested a role for the gut-brain axis in cognitive aging, and probiotics have been investigated as a potential strategy to modulate inflammatory and neurotrophic pathways. This randomized, triple-blind, placebo-controlled clinical trial evaluated the effects of 12 weeks of supplementation with a probiotic blend containing Lactobacillus and Bifidobacterium strains in older adults classified as cognitively unimpaired (CU), MCI, or AD. The study examined DNA damage, inflammatory cytokines, neurotrophic factors, and stool consistency before and after the intervention. Overall, probiotic supplementation showed limited and heterogeneous effects across outcomes. DNA damage analyses did not indicate increased alkaline or oxidative DNA damage after probiotic supplementation, supporting the absence of detectable genotoxicity over the intervention period. Changes in inflammatory and neurotrophic biomarkers were more strongly related to time and diagnostic subgroups than to treatment allocation. Exploratory findings suggested a possible subgroup-specific effect on neurotrophic markers, particularly an increase in NGF in the MCI probiotic arm, but this pattern was not consistent across the broader biomarker panel. Stool consistency did not show reliable pre- to post-intervention changes. These findings suggest that the probiotic formulation was safe from a genotoxic perspective but did not produce a generalized biological effect across inflammatory, neurotrophic, or gastrointestinal outcomes. Larger studies incorporating dietary monitoring and microbiota profiling are needed to clarify whether specific probiotic strains can influence biological pathways relevant to cognitive aging.},
}

@article {pmid42391577,
year = {2026},
author = {Bautista, JR and Goth, O and Anbari, AB and Powell, KR},
title = {Readability and Linguistic Characteristics of Alzheimer's Disease and Related Dementias Prevention, Symptom, and Treatment Information from Generative Artificial Intelligence Chatbots.},
journal = {Journal of gerontological nursing},
volume = {52},
number = {7},
pages = {7-11},
doi = {10.3928/00989134-20260608-03},
pmid = {42391577},
issn = {0098-9134},
mesh = {Humans ; *Alzheimer Disease/prevention & control/therapy ; Generative Artificial Intelligence ; *Comprehension ; *Linguistics ; *Dementia/prevention & control/therapy ; },
abstract = {PURPOSE: To examine the readability and linguistic characteristics of Alzheimer's disease and related dementias (ADRD) prevention, symptom, and treatment information from generative artificial intelligence (GenAI) chatbots.

METHOD: We analyzed 66 outputs from free-to-use GenAI chatbots. We extracted readability (word count, Fleisch Reading Ease, and Fleisch-Kincaid Grade Level) and linguistic scores (analytical thinking, clout, authenticity, and emotional tone) using Microsoft Word and the Linguistic Inquiry and Word Count software. Data were analyzed using descriptive statistics, t tests, analysis of variance, and multivariate analysis of variance.

RESULTS: ADRD information from GenAI chatbots, especially treatment information, had college-level readability. Linguistic analyses indicate a high analytical thinking score and low scores for clout, authenticity, and emotional tone.

CONCLUSION: Our sample of ADRD GenAI information exceeded recommended reading levels for patient education materials. Although the outputs exhibited logical thinking, they also included uncertain, inauthentic, and negative tones. ADRD caregivers should be aware of these characteristics when using GenAI chatbots for ADRD information-seeking.},
}

Humans
*Alzheimer Disease/prevention & control/therapy
Generative Artificial Intelligence
*Comprehension
*Linguistics
*Dementia/prevention & control/therapy

@article {pmid42391744,
year = {2026},
author = {Xin, Y and Sheng, J and Wang, L},
title = {A review of Alzheimer's disease diagnosis and prognosis models based on multimodal deep learning.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42391744},
issn = {2191-0200},
abstract = {Although some drugs have been approved for clinical treatment, early diagnosis and intervention remain the most effective strategies for managing Alzheimer's disease (AD) at present. With advances in deep learning and multimodal fusion, an increasing number of complex frameworks have been proposed. This paper systematically reviews multimodal deep learning-based models for AD diagnosis between 2020 and 2026. Beyond the technical survey, we explore how to deal with the heterogeneous modality integration and missing modality processing. From these experimental results, many models show impressive performance on public datasets. However, we have noticed a troubling problem that these "lab-perfect" results often falter when they face the chaos of the real-world. Because of the persistent black-box problem and the hidden traps of data leakage, the path to clinical use is still uphill. This work suggests that it is time to move beyond chasing tiny gains in accuracy and focus on building models that doctors can truly trust, understand, and use in real clinical settings.},
}

@article {pmid42391923,
year = {2026},
author = {Guo, H and Zheng, S and Shi, X and Wang, X and Ma, R and Li, G},
title = {VER155008 rescues cognitive impairment in P301S tauopathy mice by promoting HSPA8-mediated lipophagy.},
journal = {European journal of pharmacology},
volume = {1030},
number = {},
pages = {179107},
doi = {10.1016/j.ejphar.2026.179107},
pmid = {42391923},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (HSPA8) is upregulated in AD, which may have implications for impaired LD clearance via lipophagy. We investigated whether targeting HSPA8 with the small-molecule antagonist VER155008 alleviates tau pathology and cognitive deficits by activating lipophagy in P301S tauopathy models. P301S tau transgenic mice and HEK293T-P301S cells were utilized. Western blotting, immunohistochemistry, and immunofluorescence were performed to assess HSPA8 levels, lipophagy, tau proteins, and inflammatory markers. VER155008 or vehicle control was administered to P301S mice for four weeks, starting at seven months of age. Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic density was assessed through Golgi staining and electron microscopy. HSPA8 was elevated in P301S mice, correlating with impaired lipophagy and suppressed AMP-activated protein kinase (AMPK) activity. VER155008 treatment restored cognitive function and synaptic density. Critically, it activated lipophagy and reduced hippocampal LDs and tau pathology. Moreover, HSPA8 overexpression suppressed lipophagy and increased both LD accumulation and tau pathology. Inhibition of HSPA8 by VER155008 activates AMPK-mediated lipophagy, concurrently reducing tau pathology, oxidative stress, and neuroinflammation in AD models. These beneficial effects were eliminated by treatment with the AMPK inhibitor Compound C. This identifies the HSPA8-lipophagy axis as a promising therapeutic target for tauopathies.},
}

@article {pmid42391929,
year = {2026},
author = {Wang, Y and Sang, J and Li, H and Ren, X and Chen, C and Zheng, N and Xiao, H and Wei, Y and Xu, L and Jiang, R and Zhang, W and Xu, Z and Ge, L and Zhu, J and Xiong, B and Chen, Y and Feng, F and Sun, H},
title = {Development of potent BChE/Nrf2 modulators for Alzheimer's disease treatment via dual suppression of ferroptosis.},
journal = {European journal of medicinal chemistry},
volume = {317},
number = {},
pages = {119093},
doi = {10.1016/j.ejmech.2026.119093},
pmid = {42391929},
issn = {1768-3254},
abstract = {Targeting multiple pathological mechanisms holds significant potential for Alzheimer's disease (AD) therapy. Here, we designed 50 hybrids combining the benzimidazole-aminofurazan scaffold of a BChE inhibitor (S06-1064) with the 1,2,4-oxadiazole moiety of an Nrf2 activator (6). After four optimization rounds, S27-1046 and S27-1047 emerged as potent, selective BChE inhibitors and Nrf2 activators (S27-1046: eqBChE IC50 = 2.51 ± 1.51 nM, hBChE IC50 = 128.30 ± 16.89 nM, FP IC50 = 188.20 ± 57.11 nM, 4.73-fold ARE induced fold at 20 μM; S27-1047: eqBChE IC50 = 7.16 ± 2.96 nM, hBChE IC50 = 296.10 ± 55.78 nM, FP IC50 = 36.87 ± 23.07 nM, 7.42-fold ARE induced fold at 20 μM). They directly bind Keap1, disrupt Keap1-Nrf2 interaction, enhance antioxidant enzyme expression, and activate the GSH-GPX4 axis to inhibit Aβ-induced ferroptosis. Both compounds also protect against oxidative stress and neuroinflammation. S27-1047 showed superior Nrf2 activation and Keap1 binding, thus was selected for in vivo evaluation. In an Aβ-induced AD mouse model, S27-1047 significantly improved cognition, outperforming mono- or combination therapies. It has 12.62% oral bioavailability and crosses the BBB. This work presents multi-target agents targeting BChE, Nrf2, and ferroptosis for effective AD therapy.},
}

@article {pmid42391971,
year = {2026},
author = {Ning, Y and Chen, M and Yang, H and Jia, J},
title = {Sotagliflozin improves cognitive deficits and attenuates neuroinflammation of Alzheimer's disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {4},
pages = {e00946},
doi = {10.1016/j.neurot.2026.e00946},
pmid = {42391971},
issn = {1878-7479},
abstract = {Effective treatments for Alzheimer's disease (AD) are limited. Due to shared pathological mechanisms between AD and diabetes, antidiabetic drugs like sodium-glucose cotransporter-2 inhibitors (SGLT2is) are potential therapeutic options. Although SGLT2is have shown cognitive benefits in diabetes models, their effects in AD models are not fully established. This study aimed to evaluate the therapeutic effects of sotagliflozin (Sota), an SGLT2i, in both in vivo and in vitro AD models. The network pharmacology analysis was used to predict the potential targets and pathways of Sota. And we selected 6-month-old APP/PS1 transgenic mice to investigate the effects of Sota. Cognitive function was assessed using the Morris water maze test. Immunohistochemistry and immunofluorescence were employed to quantify amyloid-beta (Aβ) plaque deposition in the hippocampal or cortex and analyze neuronal loss. Additionally, amyloid β oligomers induction and microglial cells were used to evaluate the effects of Sota on the release of pro-inflammatory mediators and to investigate the underlying mechanisms. In vivo, Sota treatment improved cognitive impairments, reduced pro-inflammatory cytokines, inhibited microglial activation, and promoted neuronal survival. In vitro, Sota mitigated Aß oligomer-induced toxicity in microglial cells by decreasing reactive oxygen species and pro-inflammatory cytokine release. Mechanistically, Sota treatment was associated with suppression of extracellular signal-regulated kinase (ERK) signaling. Our findings suggest that Sota improved cognitive impairment and attenuates neuroinflammation in AD. Sota may be a promising candidate for the treatment of AD.},
}

@article {pmid42392137,
year = {2026},
author = {Chen, Y and Yan, F and Xiao, P and Li, X and Yu, L and Dong, S and Yao, C},
title = {Non-invasive nanosecond transcranial pulsed electric fields: a deep-penetrating, high-field stimulation that suppresses hippocampal β-amyloid and improves cognitive deficits in Alzheimer's disease model.},
journal = {Journal of neural engineering},
volume = {},
number = {},
pages = {},
doi = {10.1088/1741-2552/ae8579},
pmid = {42392137},
issn = {1741-2552},
abstract = {OBJECTIVE: Hippocampal β-amyloid (Aβ) pathology may induce early circuit dysfunction and memory impairment in Alzheimer's disease (AD), making it a key target for slowing disease progression. However, existing transcranial electrical stimulation approaches, while remaining within safety limits, are insufficient to non-invasively generate sufficiently strong electric fields in deep brain regions. Here, we investigated whether nanosecond transcranial pulsed electric field stimulation (ns-tPFS) could provide a non-invasive deep-target strategy for modulating hippocampal Aβ pathology in an AD model.

APPROACH: The 10-month-old 5xFAD mice were selected for delivering repeated ns-tPFS (500 ns, 500 V, 1 Hz). The intracranial electric field exposure was estimated using finite-element modeling (FEM). Treatment effects were evaluated using the Morris water maze, Y-maze, immunofluorescence of Aβ deposition in the hippocampus and cortex, and western blotting of Aβ-related proteins. In addition, the structural responses of Aβ oligomers to pulsed electric fields were examined by employing molecular dynamics simulations, and structural brain safety was assessed by 9.4 T small-animal MRI.

MAIN RESULTS: ns-tPFS generated transient hippocampal electric fields on the order of 104 V/m. It reduced the hippocampal Aβ burden and was associated with coordinated changes in Aβ-related pathways, including decreased amyloidogenic processing and modulated Aβ transport-related receptors. Molecular dynamics simulations further suggested that Aβ oligomers are structurally sensitive to nanosecond-scale electric field transients within the hippocampal field range estimated by FEM. These changes were accompanied by improved spatial and working memory in 5xFAD mice. In contrast, under the present stimulation regimen, healthy mice were observed with no detectable cognitive impairment, or macroscopic MRI abnormalities.

SIGNIFICANCE: ns-tPFS may be a promising non-invasive deep-target electric-field strategy for mitigating hippocampal Aβ pathology and improving cognitive performance in an AD mouse model.},
}

@article {pmid42392515,
year = {2026},
author = {Pandey, JK and Verma, SK and Kumar, J and Perwej, Y and Jha, DSK and Panchal, BY and Ferdouse, R and V, S and Banerjee, S and Tiwari, M and Badal, R and Mandal, P and Baghel, JS},
title = {Transformative Role of Advanced Neural Computation in Clinical Image Diagnostics: A Review of Key Concepts and Applications.},
journal = {Seminars in ultrasound, CT, and MR},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.sult.2026.06.010},
pmid = {42392515},
issn = {1558-5034},
abstract = {Medical imaging plays a crucial role in modern diagnostic practices, but traditional techniques often face limitations in accuracy, efficiency, and scalability. The emergence of deep learning (DL) has led to significant improvements that are transforming this field. This review discusses how DL algorithms are enhancing diagnostic imaging by improving accuracy, enabling automated analysis, and supporting personalized treatment plans. It focuses on key deep learning (DL) frameworks, including convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). The review examines their applications in important medical imaging tasks such as image classification, segmentation, reconstruction, and disease prediction. It also considers how DL techniques are integrated with tools like radiomics, data augmentation strategies, and predictive analytics models. DL methods have shown superior performance in detecting and classifying diseases like pneumonia, tuberculosis, and Alzheimer's. They also improve the quality and speed of imaging modalities such as MRI, CT, and ultrasound. Despite these advances, challenges remain in data availability, model interpretability, clinical validation, and ethical issues related to bias and privacy. Addressing these challenges is essential for the successful clinical use of DL in medical imaging. This review ends with suggestions for future directions and best practices for ethically and practically integrating DL technologies into routine healthcare.},
}

@article {pmid42392701,
year = {2026},
author = {Li, JY and Wang, XX and Wan, SF and Feng, TT and Guo, AJ and Liu, JY and Feng, K},
title = {[Research progress on role of PINK1/Parkin-mediated mitophagy in Alzheimer's disease and TCM interventions].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2143-2152},
doi = {10.19540/j.cnki.cjcmm.20260113.701},
pmid = {42392701},
issn = {1001-5302},
mesh = {Humans ; PTEN-Induced Putative Kinase ; *Protein Kinases/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Mitophagy/drug effects ; Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mitochondria/metabolism/drug effects ; },
abstract = {Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.},
}

Humans
PTEN-Induced Putative Kinase
*Protein Kinases/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology
*Ubiquitin-Protein Ligases/metabolism/genetics
*Mitophagy/drug effects
Animals
*Drugs, Chinese Herbal/administration & dosage
Mitochondria/metabolism/drug effects

@article {pmid42392719,
year = {2026},
author = {Yuan, CB and Ju, YT and Liu, YM and Wang, BS and Zhang, L and Yu, CY and Yang, YL and Chen, WY and Leng, YJ and Cheng, MJ and Min, DY},
title = {[Quercetin improves cognitive impairment in mice with Alzheimer's disease by inhibiting inflammatory response and activating cAMP/PKA/CREB signaling pathway].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2323-2334},
doi = {10.19540/j.cnki.cjcmm.20251210.801},
pmid = {42392719},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism ; Male ; *Quercetin/administration & dosage ; Signal Transduction/drug effects ; Mice ; *Cyclic AMP Response Element-Binding Protein/genetics/metabolism ; Humans ; *Cyclic AMP/metabolism/genetics/immunology ; *Cyclic AMP-Dependent Protein Kinases/genetics/metabolism ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy/genetics ; Mice, Transgenic ; Disease Models, Animal ; Hippocampus/drug effects ; },
abstract = {This study aimed to investigate the effects of quercetin on cognitive dysfunction in a mouse model of Alzheimer's disease(AD) and to explore its potential mechanisms. Network pharmacology was used to construct a "drug-core component-key target-pathways-disease" network to identify potential targets and related pathways associated with drug efficacy. Thirty 3-month-old male APP/PS1 transgenic mice were randomly divided into a model group, a quercetin group(100 mg·kg~(-1)), and a donepezil hydrochloride group(0.5 mg·kg~(-1)), while age-matched C57BL/6J mice from the same litter served as the control group. Each group consisted of 10 mice, and the treatment groups received the corresponding drug interventions for 24 weeks. The Morris water maze(MWM) test was used to assess memory performance, and the nest-building test was applied to evaluate daily living ability. hematoxylin-eosin(HE) staining, Nissl staining, and immunohistochemistry were used to assess pathological changes in hippocampal neurons. Western blot analysis was used to detect the expression levels of tau, phosphorylated(p)-tau, interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), brain-derived neurotrophic factor(BDNF), cyclic adenosine monophosphate(cAMP), protein kinase A(PKA), p-PKA, cAMP response element-binding protein(CREB), and p-CREB-related signaling proteins in hippocampal tissue. Network pharmacology analysis identified 165 quercetin-related active component targets and 4 324 learning-and memory-related targets. Intersection analysis yielded 71 AD-related core genes. Protein-protein interaction(PPI) network analysis identified protein kinase B(Akt1), estrogen receptor 1(ESR1), epidermal growth factor receptor(EGFR), and non-receptor tyrosine kinase(SRC) as core target genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicated that quercetin may regulate AD progression through the PI3K/Akt signaling pathway, cAMP signaling pathway, TNF signaling pathway, and EGFR tyrosine kinase inhibitor resistance-related pathways. Animal experiments showed that, compared with the control group, the model group exhibited significantly reduced nesting scores, prolonged escape latency(P<0.05), and fewer platform crossings(P<0.05). The number of neurons in the cortex and hippocampus was significantly decreased, and extracellular amyloid β(Aβ) deposition was significantly increased(P<0.01). In addition, the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly elevated(P<0.01), whereas BDNF protein expression was significantly reduced(P<0.01). Compared with the model group, the quercetin and donepezil hydrochloride groups showed significantly increased nesting scores, shortened escape latency(P<0.05), and increased numbers of platform crossings(P<0.05). The number of neurons in the hippocampal CA1 region was significantly increased(P<0.01), and the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly decreased(P<0.05, P<0.01). These results indicate that quercetin can significantly improve cognitive impairment in APP/PS1 transgenic mice, and its mechanism may be associated with activation of the cAMP/PKA/CREB signaling pathway and reversal of the upregulation of pro-inflammatory cytokines, including TNF-α and IL-1β.},
}

Animals
*Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism
Male
*Quercetin/administration & dosage
Signal Transduction/drug effects
Mice
*Cyclic AMP Response Element-Binding Protein/genetics/metabolism
Humans
*Cyclic AMP/metabolism/genetics/immunology
*Cyclic AMP-Dependent Protein Kinases/genetics/metabolism
Mice, Inbred C57BL
*Cognitive Dysfunction/drug therapy/genetics
Mice, Transgenic
Disease Models, Animal
Hippocampus/drug effects

@article {pmid42392731,
year = {2026},
author = {Lyu, SY and Wang, XZ and Chen, XY and Guo, R},
title = {[Exploring mechanism of "treating different diseases with the same method" for depression and Alzheimer's disease based on "liver-spleen-kidney" axis and advances in traditional Chinese medicine intervention].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {10},
pages = {2726-2738},
doi = {10.19540/j.cnki.cjcmm.20260108.302},
pmid = {42392731},
issn = {1001-5302},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; *Drugs, Chinese Herbal/administration & dosage/therapeutic use ; *Spleen/drug effects/physiopathology ; *Kidney/drug effects/physiopathology ; *Liver/drug effects/physiopathology ; Animals ; *Medicine, Chinese Traditional ; *Depression/drug therapy/physiopathology ; },
abstract = {Depression(major depressive disorder, MDD) and Alzheimer's disease(AD) are two highly prevalent neuropsychiatric disorders. With the aging population, their comorbidity rate continues to rise. The pathogenesis of MDD and AD is complex, and modern medicine still lacks strategies that can simultaneously intervene in the core processes of both diseases. The theory of "treating different diseases with the same method" in traditional Chinese medicine(TCM) is an important therapeutic principle, which means that different diseases showing identical syndromes during their development can be treated with the same approach. This provides a TCM perspective for the diagnosis and treatment of their comorbidity. Based on the theory of the "liver-spleen-kidney" axis, this study identified that MDD and AD shared common pathogenesis: liver dysfunction in free coursing, spleen dysfunction in transportation, and kidney essence deficiency. It further connected this pathogenesis with the dysregulation of the neuroendocrine-immune(NEI) network in modern medicine, revealing common pathological mechanisms in neuroinflammation, dysfunction of the "hypothalamic-pituitary-adrenal"(HPA) axis, and gut microbiota dysbiosis. Meanwhile, it also reviewed specific mechanisms of TCM herbs such as Bupleuri Radix(Chaihu), Paeoniae Radix Alba(Baishao), and Astragali Radix(Huangqi), as well as their active components, in treating MDD and AD by regulating the NEI network through multiple targets and pathways. This may provide evidence for the application of the "treating different diseases with the same method" theory and broaden the perspective for the treatment of MDD and AD.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/metabolism
*Drugs, Chinese Herbal/administration & dosage/therapeutic use
*Spleen/drug effects/physiopathology
*Kidney/drug effects/physiopathology
*Liver/drug effects/physiopathology
Animals
*Medicine, Chinese Traditional
*Depression/drug therapy/physiopathology

@article {pmid42381088,
year = {2026},
author = {Verberk, IMW and de Koning, LA and Coomans, EM and Trieu, C and Leeuwis, AE and Hunter, J and Honigberg, L and van der Flier, WM and Vijverberg, EGB and Ossenkoppele, R and van de Giessen, E and Teunissen, CE},
title = {The potential of key Alzheimer's plasma biomarkers to mimic tau PET MUBADA-based disease staging.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02085-6},
pmid = {42381088},
issn = {1758-9193},
abstract = {BACKGROUND: Patients with Alzheimer's disease (AD) with a low to intermediate tau-PET burden might benefit most from anti-amyloid treatment. Staging tau burden with plasma biomarkers would offer a scalable alternative to staging with tau-PET. This study investigated whether key plasma biomarkers P-tau217, P-tau181, Aβ42/40, GFAP and NfL can be used to accurately stage amyloid status (A-/A+) and tau-PET burden, and evaluated the relation of such a plasma-based staging system with cognitive outcomes over time.

METHODS: We included 105 participants with subjective cognitive decline (n = 27 A-, n = 18 A+), A+ mild cognitive impairment (n = 10) or A + AD-dementia (n = 50) from the Amsterdam Dementia Cohort who underwent [[18]F]flortaucipir PET-burden assessment (Tlow, Tintermediate or Thigh; based on MUBADA SUVr) and longitudinal cognitive assessment (average follow-up: 4.1 ± 3.5 years). AD-related plasma biomarkers were measured with Simoa. Discriminative performance (AUC) of each marker was compared using ROC analysis, and combined utility was assessed with logistic regression. Subsequently, cutoffs were established aiming for 90%-specificity, to regroup participants into a plasma-based staging scheme. Age-, sex- and education-adjusted linear mixed models (LMM) were performed to compare associations of plasma versus PET-based staging with longitudinal cognition.

RESULTS: 27 participants were A-TPET_low, 22 A+TPET_low, 27 A+TPET_int and 29 A+TPET_high. To discriminate A-TPET_low participants from A+TPET_low/int participants, P-tau217 performed best among all measured markers P-tau217, P-tau181, Aβ42/40, GFAP and NfL (AUC = 0.92 [95% CI: 0.856-0.985]). To discriminate A+TPET_high participants from A+TPET_low/int participants, also P-tau217 performed best among all markers (AUC = 0.74 [95% CI: 0.618-0.862]). A combination of Wald's backward-selected plasma markers did not statistically improve discriminative performance (DeLong's p > 0.05; two-marker combinations selected). Applying two cutoffs for P-tau217 as well as for the two-marker combinations, at 90% specificity to discriminate subsequent groups, we derived two plasma-based staging schemes. While the tau-PET staging scheme significantly and consistently associated with cognitive performance and decline across cognitive domains in LMMs, the plasma staging schemes did not.

CONCLUSIONS: Performance of plasma-based staging approaches developed in this study were high when discriminating individuals without amyloid pathology, while this was moderate when discriminating amyloid positive individuals with a high tau-PET burden. Our LMM findings visualize that tau staging in amyloid-positive individuals remains optimally performed with tau-PET scans.},
}

@article {pmid42381140,
year = {2026},
author = {Li, Y and Xie, K and Qian, S and Wang, Z and Zhang, H and Si, L},
title = {Quantifying Short-Term Functional Changes After Lecanemab Treatment in Early Alzheimer's Disease: An Exploratory 3-Month Follow-Up Case Report Using Eye Movement and Gait Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050471024260520113701},
pmid = {42381140},
issn = {1875-5828},
abstract = {INTRODUCTION: Lecanemab is a monoclonal antibody targeting amyloid-β (Aβ) and is currently used in clinical practice for the treatment of early Alzheimer's disease (AD). However, noninvasive biomarkers reflecting its early efficacy are still unclear. This exploratory case report aims to investigate the combination of eye movement and gait analysis to quantitatively monitor shortterm functional changes during lecanemab treatment.

CASE PRESENTATION: Two male patients, both diagnosed with mild Alzheimer's disease through amyloid- PET and both with the APOE ε3/ε3 genotype, received intravenous lecanemab (10 mg/kg, every two weeks) for three months. Cognitive assessments (Montreal Cognitive Assessment, Mini- Mental State Examination, Clinical Dementia Rating), eye movement tests (smooth pursuit, overlapping saccades, anti-saccades), and gait analysis under single-task and dual-task conditions were conducted at baseline and follow-up. Patient 1 (79 years old) showed stable cognitive function, significant improvement in multiple eye movement parameters, and partial improvement in gait under single-task conditions. Patient 2 (60 years old) did not follow up on cognitive function tests as scheduled and showed inconsistent changes in eye movement parameters, but improved selected gait measures under dual-task conditions, particularly a shorter turning time. Neither patient experienced Amyloid-Related Imaging Abnormalities or infusion-related adverse events during the infusion process.

CONCLUSION: This exploratory case report suggests that eye movement and gait analysis may be sensitive to short-term functional changes following lecanemab treatment, which were not consistently captured by traditional cognitive scales. These findings are hypothesis-generating and warrant further investigation in larger studies. Multimodal functional assessment may hold promise as a tool for monitoring early treatment effects in Alzheimer's disease.},
}

@article {pmid42381141,
year = {2026},
author = {Mehrabadi, S},
title = {The Role of Digital Health Technologies in Early Detection and Management of Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050415800251226061142},
pmid = {42381141},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and functional impairment, posing significant challenges for early detection and management. In recent years, digital health technologies have emerged as promising tools to enhance the diagnosis, monitoring, and treatment of AD. This review paper explores the multifaceted role of digital health technologies in the early detection and management of Alzheimer's disease. We examine the use of wearable devices that monitor cognitive function and daily activities, as well as mobile health applications designed for cognitive training and symptom tracking. Additionally, we analyze the impact of telehealth services in providing remote care, particularly for underserved populations. The integration of artificial intelligence and machine learning for analyzing behavioral and cognitive data to support early diagnosis and risk assessment is also discussed. Furthermore, we explore the concept of digital biomarkers and their potential to complement traditional diagnostic methods. Ethical considerations surrounding privacy, data security, and informed consent are addressed to ensure responsible implementation of these technologies. Finally, we highlight gaps in current research and propose future directions for integrating digital health technologies into Alzheimer's care, emphasizing the potential for personalized interventions tailored to individual patient needs. This review underscores the transformative potential of digital health to reshape Alzheimer's disease management and improve patient outcomes.},
}

@article {pmid42382036,
year = {2026},
author = {Hofmann, A and Paczynski, M and Ponisio, MR and Saef, B and Roberts, JP and Powell, WJB and Gupta, A and Oh, I and Hofford, M and Posey, Z and Aldinger, M and Benzinger, TLS and Morris, JC and Snider, BJ and Schindler, SE},
title = {Performing multiple biomarker tests delays initiation of amyloid-targeting treatments.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70387},
pmid = {42382036},
issn = {2352-8729},
abstract = {INTRODUCTION: With the clinical availability of amyloid-targeting treatments (ATTs), accurate and timely biomarker-based diagnosis of Alzheimer's disease (AD) has become increasingly important. Three AD biomarker modalities are commonly available in clinical practice: amyloid positron emission tomography (PET), cerebrospinal fluid (CSF) tests, and blood tests.

METHODS: We investigated the use and agreement of different biomarker modalities in a memory clinic. Further, we calculated the time until ATT initiation for patients who underwent a single test versus multiple biomarker tests.

RESULTS: The blood test agreed with amyloid PET in nine of 11 patients and CSF tests in all 14 patients. The median time from first clinic visit to ATT initiation was 4.7 months in 209 patients who underwent a single test and 8.1 months in 12 patients who underwent multiple tests.

DISCUSSION: Performing multiple biomarker tests delays initiation of ATT and should be restricted to patients with uncertain amyloid status following the first biomarker test.},
}

@article {pmid42382677,
year = {2026},
author = {Siam, NH and Nasrin, N and Saiyara, S and Saha, H and Deb, DP and Islam, J},
title = {Medicinal Plants and Their Bioactive Phytochemicals as Emerging Therapeutic Strategies for Alzheimer's Disease: An Integrative Review of Preclinical and Clinical Evidence.},
journal = {Scientifica},
volume = {2026},
number = {},
pages = {6124916},
pmid = {42382677},
issn = {2090-908X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and blood-brain barrier disruption, collectively leading to widespread cortical and subcortical atrophy. Current FDA-approved pharmacotherapies, including acetylcholinesterase inhibitors and memantine, provide only modest symptomatic relief and fail to halt disease progression, underscoring the urgent need for alternative therapeutic approaches. Growing evidence highlights medicinal plants and their bioactive phytoconstituents as promising candidates for AD prevention and treatment because of their multitarget mechanisms, favorable safety profiles, and long history of traditional use. This review synthesizes extensive in vitro, in vivo, and clinical studies demonstrating the neuroprotective potential of plant extracts and isolated compounds that exert antioxidant, anti-inflammatory, antiamyloidogenic, anti-tau, cholinesterase-inhibitory, and synaptic-modulating effects. Key medicinal species, including Abelmoschus esculentus, Brassica oleracea, Cannabis sativa, Citrus reticulata, Lantana camara, Launaea taraxacifolia, Lawsonia inermis, Marrubium vulgare, Markhamia lutea, Persicaria minor, Pithecellobium dulce, Salvia aristata, Trigonella foenum-graecum, and Withania somnifera, show significant cognitive and neuroprotective benefits in experimental AD models. Phytochemicals such as sulforaphane, nobiletin, trigonelline, diosgenin, verbascoside, withaferin A, and withanolides strongly modulate the amyloid, tau, oxidative, and inflammatory pathways. Clinical trials further support the therapeutic potential of several plant-derived interventions for mild cognitive impairment and AD-related dementia. Collectively, these findings highlight medicinal plants and their active constituents as compelling complementary or translational strategies for AD management, warranting further mechanistic and clinical validation. This review aims to evaluate the neuroprotective potential of medicinal plants and their bioactive compounds in preventing and managing AD by summarizing evidence from in vitro, in vivo, and clinical studies.},
}

@article {pmid42382756,
year = {2026},
author = {Xing, JF and Mu, K and Yan, X and Yang, X and Zhang, D and Gao, W and Zhang, T and Yang, S and Wang, R and Zhang, W and Zhu, Y},
title = {Calibrating microglia states in Alzheimer's disease: decoding immune-metabolic networks and nano-targeted multicomponent therapies.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1843978},
pmid = {42382756},
issn = {1664-3224},
mesh = {*Alzheimer Disease/metabolism/immunology/therapy/pathology ; Humans ; *Microglia/metabolism/immunology/pathology/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Metabolic Networks and Pathways ; },
abstract = {Alzheimer's disease treatment is shifting from pathology removal to regulating the brain microenvironment. Anti-Aβ monoclonal antibodies, such as lecanemab and donanemab, provide statistically significant disease-modifying effects but offer only modest cognitive improvement and pose safety risks, including amyloid-related imaging abnormalities. These results show that amyloid clearance is clinically relevant but not sufficient for full restoration of neuroimmune, metabolic, synaptic, and neurovascular balance. Microglia are now seen as central to Alzheimer's disease susceptibility and progression, existing along dynamic, spatially organized, sex-influenced, and genetically determined continua beyond a simple pro- or anti-inflammatory state. This review calls out three key drivers of microglial dysfunction: the TREM2-APOE lipid-sensing axis, complement-mediated synaptic elimination, and immunometabolic reprogramming-including glycolysis, mitochondrial damage, autophagy failure, NAD+ depletion, and innate immune signaling. We examine natural bioactive compounds, metabolic modulators, and biomimetic nanodelivery as promising, yet currently unproven, strategies for adjusting microglial state. Future therapies should incorporate both pathology removal and microenvironment protection, tailored by disease stage, genetic profile, sex, vascular risk, and microglial state-associated biomarkers.},
}

*Alzheimer Disease/metabolism/immunology/therapy/pathology
Humans
*Microglia/metabolism/immunology/pathology/drug effects
Animals
Amyloid beta-Peptides/metabolism
Metabolic Networks and Pathways

@article {pmid42384283,
year = {2026},
author = {Mostafa, SS and Mohammed, RA and Abbas, AY and Othman, MA},
title = {The protective role of melatonin on the brain in a rat model of Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42384283},
issn = {1573-7365},
mesh = {Animals ; *Melatonin/pharmacology/therapeutic use ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology/prevention & control ; Male ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Brain/drug effects/metabolism/pathology ; Disease Models, Animal ; Aluminum Chloride ; Maze Learning/drug effects ; Microglia/drug effects/metabolism ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {Alzheimer's disease is an age-related neurodegenerative disorder characterized by progressive cognitive decline and multiple biochemical and structural abnormalities in the brain. Accumulating evidence suggests that aluminum exposure may contribute to neurodegenerative process including those observed in AD and was linked to neuronal damage and cognitive impairment. Melatonin (Mel) is a neurohormone that regulates circadian rhythm and possesses antioxidant, anti-inflammatory and neuroprotective properties. The current study investigated the potential protective roles of Mel in a rat model of AD induced by aluminum chloride (AlCl3). Forty adult male rats were divided into 4 experimental groups: a control group, an AlCl3-treated group, an AlCl3+Mel-treated group, and a Mel-only group. AlCl3 was administered orally for four weeks. Cognitive performance and spatial learning were assessed using Morris water maze test. Plasma levels of the pro inflammatory cytokines; interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured using enzyme linked immunosorbent assay. Histopathological examination of the frontal cortex was performed using hematoxylin and eosin staining, and immunohistochemistry was conducted using the neuronal marker NeuN, microglial marker Iba1, and inflammatory markers IL-6 and TNF-α. Mel treatment significantly improved learning and memory performance in the Morris water maze test. It also reduced plasma levels of IL-6 and TNF-α. Using immunohistochemistry, Mel increased NeuN expression, while reducing Iba1, IL-6 and TNF-α expression. These findings showed that Mel attenuated frontal cortical neurodegeneration and neuroinflammation in this model of AD, suggesting that Mel may represent a promising neuroprotective therapeutic strategy for AD.},
}

Animals
*Melatonin/pharmacology/therapeutic use
*Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology/prevention & control
Male
Rats
*Neuroprotective Agents/pharmacology/therapeutic use
*Brain/drug effects/metabolism/pathology
Disease Models, Animal
Aluminum Chloride
Maze Learning/drug effects
Microglia/drug effects/metabolism
Rats, Sprague-Dawley
Tumor Necrosis Factor-alpha/metabolism

@article {pmid42385118,
year = {2026},
author = {Morrill, VN and Pike, JR and Hu, J and Fornage, M and Surapaneni, A and Walker, KA and Knopman, DS and Mosley, TH and Coresh, J and Schneider, ALC and Smith, JR and Gottesman, RF},
title = {Genetic Risk for Alzheimer Disease, Midlife Hypertension, and Dementia: The ARIC Neurocognitive Study.},
journal = {Neurology},
volume = {107},
number = {2},
pages = {e218280},
doi = {10.1212/WNL.0000000000218280},
pmid = {42385118},
issn = {1526-632X},
mesh = {Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/genetics/epidemiology ; Black or African American/genetics ; *Dementia/genetics/epidemiology ; *Genetic Predisposition to Disease ; Genetic Risk Score ; *Hypertension/genetics/epidemiology ; Incidence ; Prospective Studies ; Risk Factors ; United States/epidemiology ; White ; },
abstract = {BACKGROUND AND OBJECTIVES: Genetics represent a nonmodifiable risk factor for Alzheimer disease (AD), with 60%-80% heritability. Midlife hypertension is a modifiable risk factor for both dementia and death. Our primary objective was to determine how genetic risk for AD modifies the association between hypertension and dementia.

METHODS: The Atherosclerosis Risk in Communities Study is an ongoing community-based prospective cohort study of 4 US centers. We analyzed White and Black participants free of dementia at age 55 years with genotypes and blood pressure measured at visit 1 (1987-1989). Three genetic risk groups (low, medium, high) were defined based on tertiles of a race-specific AD polygenic risk score. Dementia was ascertained through cognitive testing, informant interviews, hospitalization, codes and death records. Death was ascertained through the National Death Index. We examined the association of midlife hypertension with incident dementia within 3 genetic risk groups using Cox proportional-hazards and cumulative incidence function estimations. We used age 55 years as the time origin, with left truncation to allow entry at ages older than 55 years; age on December 31, 2022, was the administrative censoring date.

RESULTS: Among 8,931 White and 2,666 Black participants, the median follow up time was 26.6 and 23.8 years, the mean age was 54.0/53.5 years, and 53.0%/62.5% were female, respectively. After adjusting for demographics, midlife hypertension was significantly associated with dementia incidence across all genetic risk groups among White participants (low risk hazard ratio [HR] 1.29; 95% CI 1.07-1.55, medium risk HR 1.34; 95% CI 1.13-1.58, high risk HR 1.19; 95% CI 1.03-1.38) and among Black participants at high genetic risk (HR 1.31; 95% CI 1.04-1.66). Associations for low and medium genetic risk Black participants were consistent but not statistically significant. There were no significant differences in association of hypertension with dementia by AD genetic risk group. Individuals with hypertension had a 0%-2% higher probability of developing dementia by age 80 and a 6%-13% lower probability of dementia-free survival to age 80 years vs those without hypertension, across race and genetic risk groups.

DISCUSSION: Genetic risk for AD does not modify the association between hypertension and dementia. These data support the fact that all individuals with hypertension are likely to benefit from antihypertensive treatment.},
}

Female
Humans
Male
Middle Aged
*Alzheimer Disease/genetics/epidemiology
Black or African American/genetics
*Dementia/genetics/epidemiology
*Genetic Predisposition to Disease
Genetic Risk Score
*Hypertension/genetics/epidemiology
Incidence
Prospective Studies
Risk Factors
United States/epidemiology
White

@article {pmid42385584,
year = {2026},
author = {Kiprov, DD and Green, AP and Boyinapalli, P},
title = {Technological advances in selective plasma adsorption: The MTx.100 column and the emergence of subtractive precision medicine.},
journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis},
volume = {65},
number = {4},
pages = {104484},
doi = {10.1016/j.transci.2026.104484},
pmid = {42385584},
issn = {1473-0502},
abstract = {Therapeutic plasma exchange (TPE) is well-established for autoimmune, hematological, and neurological disease but is intrinsically non-selective: protective immunoglobulins, coagulation factors, and albumin are depleted alongside pathogenic substances, and reliance on donor-derived replacement fluid carries logistical and immunological costs. The MTx.100 column (Marker Therapeutics AG) is a selective plasma adsorption device that addresses these limitations through hydrophobic-affinity adsorption. It targets pro-inflammatory cytokines, protein-bound metabolic waste, hydrophobic environmental contaminants, and microparticulates while preserving immunoglobulins, coagulation factors, electrolytes, and the patient's own signaling proteins. Plasma is treated and conserved, eliminating replacement-fluid dependency. Clinical experience encompasses approximately 1000 procedures globally. A prospective single-arm multicenter trial in 107 critically ill COVID-19 patients (424 procedures) demonstrated 28-day mortality of 37.4% against an FDA-agreed performance goal of 88.1% (p < 0.0001); propensity-matched analysis showed approximately three-fold higher survival odds versus standard of care (OR 3.0; 95% CI 1.56-5.85; p = 0.0008), with significant reductions in inflammatory and metabolic markers and no serious adverse events attributable to the column or procedure. Hospital case reports across polytrauma, post-LVAD implantation, and toxin-induced hepatitis demonstrated hemodynamic and electrolyte stability and favorable clinical trajectories. Across 114 elective outpatient procedures, vital signs and electrolytes remained stable throughout treatment, and third-party laboratory analyses confirmed measurable reduction of PFAS, microplastics, and persistent organic pollutants in treated patients. Within the emerging framework of subtractive precision medicine, selective plasma adsorption offers a complementary paradigm to additive pharmacotherapy for conditions characterized by inflammatory and toxic burden. A pilot trial in Alzheimer's disease is underway.},
}

@article {pmid42385644,
year = {2026},
author = {Luo, J and Rasmussen, IJ and Thomassen, JQ and Frikke-Schmidt, R},
title = {Causal insights of modifiable cardiovascular risk factors for dementia risk - potential for efficient prevention and improved brain health.},
journal = {Atherosclerosis},
volume = {419},
number = {},
pages = {120824},
doi = {10.1016/j.atherosclerosis.2026.120824},
pmid = {42385644},
issn = {1879-1484},
abstract = {BACKGROUND: The 2024 Lancet Commission report identifies 14 modifiable risk factors that may prevent half of dementia. The causal nature of these associations remains however unclear. We aimed to establish robust causal estimates for modifiable cardiovascular risk factors and dementia, offering tangible targets for effective dementia prevention.

METHODS: We selected independent variants from the largest genomic consortia to date (N = 439,214 to 3,037,499) for each modifiable risk factor and generated polygenic risk scores for participants of European ancestry in the UK Biobank (N = 408,788). We conducted univariable and multivariable linear Mendelian randomization, assessed genetic shapes by nonlinear approaches, and performed several sensitivity analyses, including sex stratification.

RESULTS: Genetic predisposition to high low-density-lipoprotein cholesterol (LDL-C) (1.12, 1.01-1.23), non-high-density-lipoprotein cholesterol (1.30, 1.26-1.35), triglycerides (1.19, 1.01-1.41), body mass index (1.04, 1.02-1.07), systolic (1.14, 1.09-1.20) and diastolic (1.10, 1.02-1.19) blood pressure, type 2 diabetes (1.04, 1.00-1.09) and smoking (1.18, 1.06-1.32), were associated with increased risk of all-cause dementia, while longer education was associated with a reduced risk (0.58, 0.33-0.99). Results for Alzheimer's disease and vascular dementia were directionally similar. Moreover, genetically predicted high physical activity level was associated with low risk of Alzheimer's disease (0.58, 0.33-0.99) only. Sensitivity analyses supported the main results, and no nonlinear shapes were detected.

CONCLUSION: These findings provide causal insights into modifiable cardiovascular risk factors for dementia and unfold a substantial potential for dementia prevention by timely treatment of high LDL-C, triglycerides, hypertension, and diabetes, alongside smoking cessation and maintenance of normal weight.},
}

@article {pmid42386905,
year = {2026},
author = {Chun, H and Youn, W and Lim, H and Harada, R and Ko, HY and Yoon, J and Oh, SJ and Seemann, P and Pepe, JG and Shoichet, BK and Lee, HW and Furumoto, S and Okamura, N and Yun, M and Lee, CJ},
title = {In-depth multimodal validation of [18]F-THK5351 for imaging monoamine oxidase-B-mediated reactive astrogliosis in Alzheimer's and related neurodegenerative diseases.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {42386905},
issn = {2092-6413},
support = {RS-2025-16071448//National Research Foundation of Korea (NRF)/ ; RS-2022-00144475//National Research Foundation of Korea (NRF)/ ; RS-2025-00520546//National Research Foundation of Korea (NRF)/ ; RS-2022-00144475//National Research Foundation of Korea (NRF)/ ; RS-2024-00403076//Korea Basic Science Institute (KBSI)/ ; },
abstract = {[18]F-THK5351, initially developed as a positron-emission tomography (PET) tracer for tau pathology, was later shown to display high affinity for monoamine oxidase-B (MAO-B), raising uncertainty about the biological origin of its brain signals in neurodegenerative diseases. To resolve this ambiguity, we implemented a multi-scale validation framework integrating enzyme activity inhibition assays, molecular docking, biolayer interferometry, autoradiography, multiple transgenic and viral animal models, and human PET imaging. THK5351 selectively inhibited MAO-B while sparing MAO-A and exhibited reversible binding kinetics to recombinant MAO-B. Computational modelling localized THK5351 near the MAO-B substrate funnel, revealing moderate binding energy and weaker π-π stacking interactions compared with selective tau tracers. Autoradiographic analysis of human cortical tissue demonstrated that tracer binding was dominated by MAO-B-related signals, with a smaller contribution from tau aggregates, a difference insufficient to produce visually distinguishable patterns in clinical imaging. In APP/PS1 mice, [18]F-THK5351 uptake colocalized with regions of reactive astrogliosis and was abolished by MAO-B inhibition, whereas overexpression of P301L-hTau induced extensive tau deposition without affecting tracer retention. MAO-B knockout reduced both tracer binding and tau phosphorylation, and viral induction of astrogliosis elevated tracer uptake that was reversed by selective MAO-B blockade. In a patient with corticobasal syndrome, tracer signals decreased during selegiline treatment and reappeared after drug withdrawal, mirroring preclinical pharmacological responses. Collectively, these findings demonstrate that [18]F-THK5351 uptake primarily reflects MAO-B-mediated reactive astrogliosis rather than tau pathology, providing mechanistic insight into its signal origin and underscoring the value of cross-scale, multimodal validation in PET tracer development for neurodegenerative disease research.},
}

@article {pmid42387856,
year = {2026},
author = {Miles, N and McNamee, B and Zadikoff, C and Boiser, J and Shebley, M and Boinpally, R},
title = {Comparison of ABBV-552 Safety and Pharmacokinetics in Healthy Asian and Western Adults.},
journal = {Clinical pharmacology in drug development},
volume = {15},
number = {7},
pages = {e70072},
doi = {10.1002/cpdd.70072},
pmid = {42387856},
issn = {2160-7648},
support = {//AbbVie/ ; },
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; *Alzheimer Disease/drug therapy/physiopathology ; Asian People ; Dose-Response Relationship, Drug ; Healthy Volunteers ; *Membrane Glycoproteins/agonists ; *Nerve Tissue Proteins/agonists ; White People ; },
abstract = {ABBV-552, a positive modulator of synaptic vesicle glycoprotein 2A (SV2A), was under investigation as a treatment for cognitive impairment related to Alzheimer's disease. This Phase 1, multicenter, open-label, parallel cohort study (NCT05686980) was conducted to examine the pharmacokinetics (PK), safety, and tolerability of ABBV-552 in healthy adult Japanese and Han Chinese participants and to compare PK and safety findings with healthy adult Western participants from previous studies. Japanese participants in Cohort 1 (N = 10) received three ascending single oral doses (5, 15, and 40 mg) of ABBV-552 with a washout of 7 days between doses. Han Chinese participants in Cohort 2 (N = 7) received a single oral dose of 40 mg ABBV-552. After a single oral dose of 40 mg ABBV-552, PK was comparable between both cohorts. Additionally, the range of individual ABBV-552 concentrations and mean 24-h profiles were comparable with historical data in healthy adult Western participants. In this small study population, single doses of ABBV-552 were well tolerated at all tested doses. Common adverse events reported were dizziness (39%), somnolence (11%), and fatigue (11%). No unique safety signals following single dose ABBV-552 administration were observed in the Japanese or Han Chinese populations examined compared with the previously examined Western population.},
}

Adult
Female
Humans
Male
Middle Aged
Young Adult
Administration, Oral
*Alzheimer Disease/drug therapy/physiopathology
Asian People
Dose-Response Relationship, Drug
Healthy Volunteers
*Membrane Glycoproteins/agonists
*Nerve Tissue Proteins/agonists
White People

@article {pmid42388101,
year = {2026},
author = {Lai, HY and Meng, LC and Ye, YJ and Chen, HM and Chen, LK and Hsiao, FY},
title = {Comparative risk of ventricular arrhythmia and sudden cardiac death among acetylcholinesterase inhibitors in dementia: A population-based cohort study.},
journal = {British journal of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1002/bcp.70656},
pmid = {42388101},
issn = {1365-2125},
support = {MOST 110-2634-F-010-001//Taiwan Ministry of Science and Technology/ ; NSTC111-2622-8-A49-019-IE//Taiwan National Science and Technology Council/ ; NSTC112-2923-B-A49-002-MY2//Taiwan National Science and Technology Council/ ; //Interdisciplinary Research Center for Healthy Longevity of National Yang Ming Chiao Tung University/ ; },
abstract = {BACKGROUND: Previous studies have suggested that acetylcholinesterase inhibitors (AChEIs) may be associated with an increased risk of ventricular arrhythmia or sudden cardiac death, potentially related to QTc prolongation. However, evidence comparing the real-world risk of severe cardiac conduction outcomes among the three AChEIs-donepezil, galantamine and rivastigmine-remains limited.

OBJECTIVE: This study aimed to compare the risk of ventricular arrhythmia or sudden cardiac death associated with the use of different AChEIs in older adults with dementia.

METHODS: We conducted a retrospective cohort study using Taiwan's National Health Insurance database. Older adults diagnosed with dementia who initiated AChEI therapy between 2010 and 2019 were identified and categorized according to the AChEI prescribed. Participants were followed until the end of 2020. Stabilized inverse probability of treatment weighting was applied to balance baseline characteristics, with rivastigmine serving as the reference group. Cox proportional hazards models were used to estimate hazard ratios for ventricular arrhythmia or sudden cardiac death.

RESULTS: A total of 66 589 older adults with dementia initiating AChEI therapy were included. Donepezil was the most frequently prescribed AChEI (64.8%), followed by rivastigmine (33.0%) and galantamine (2.3%). Compared with rivastigmine, IPTW-weighted analyses showed no significant association between donepezil use (HR 0.95, 95% CI, 0.82-1.09) or galantamine use (HR 1.40, 95% CI, 0.90-2.18) and the risk of ventricular arrhythmia or sudden cardiac death.

CONCLUSIONS: The risk of ventricular arrhythmia or sudden cardiac death was comparable among donepezil, galantamine and rivastigmine in older patients with dementia.},
}

@article {pmid42388121,
year = {2026},
author = {Schwartz, NU and Dietz, CD and Lin, Z and Tammewar, G and Bui, N and La Joie, R and Wang, Y and Sreekrishnan, A and Suhami, D and VandeVrede, L and Ljubenkov, PA and Rojas, JC},
title = {Reduced diffusion associated with amyloid-related imaging abnormalities in three patients treated with donanemab.},
journal = {Neurocase},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/13554794.2026.2695021},
pmid = {42388121},
issn = {1465-3656},
abstract = {Amyloid-related imaging abnormalities (ARIA) with edema (ARIA-E) and with hemorrhage (ARIA-H) are common adverse effects of amyloid-targeting therapies (ATT), characterized on MRI by T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities and susceptibility-sensitive hypointensities, respectively. ARIA resulting from ATT is not commonly associated with reduced diffusion or acute infarcts. In this case series, we describe three patients with mild cognitive impairment due to Alzheimer's disease (AD) - a 75-year-old woman, a 74-year-old woman, and an 80-year-old man (APOE ε3/ε3, ε4/ε4, and ε3/ε4, respectively) - who developed ARIA accompanied by transient foci of reduced diffusion within the first six months of donanemab treatment, without permanent T2/FLAIR correlates. The diffusion-restricting lesions may represent ischemic infarcts, although the lack of permanent T2/FLAIR correlate is atypical. Clinicians should be aware that reduced diffusion may accompany ARIA. The course can be highly dynamic, and both the clinical presentation and management implications may vary.},
}

@article {pmid42388698,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Bates, D and Showalter, J and Tobyne, S and Pascual-Leone, A},
title = {Initial specialist validation of clinical decision support recommendations from a machine learning-enabled digital cognitive assessment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1806000},
pmid = {42388698},
issn = {1664-2295},
abstract = {INTRODUCTION: Disease-modifying therapies for Alzheimer's disease (AD) heighten demand for scalable tools enabling primary care providers (PCPs) to detect cognitive impairment and triage patients for appropriate evaluation. The brief tablet-based Linus Health Core Cognitive Evaluation (CCE) integrates the Digital Clock and Recall (DCR) and Life and Health Questionnaire (LHQ) to generate clinical decision support (CDS) and decision-tree pathways.

METHODS: We conducted a retrospective specialist content-validity study (June 15-27, 2023) using a modified RAND/UCLA Appropriateness Method. Five board-certified cognitive/behavioral neurologists independently rated CDS recommendations and nine predefined pathway parts for patients aged ≥55 across 21 de-identified reports. Items scored 1-9 were summarized as pooled medians with interquartile ranges; medians ≥7 indicated appropriateness. Agreement among experts was quantified using ICC [2,k] and ICC [2,1].

RESULTS: All cognitive-impairment recommendations met the threshold. All seven borderline/impaired-DCR pathways were appropriate (median 7-8). Two pathways fell below threshold: cognitively unimpaired individuals with Green DCR scores (median 6) and a preliminary anti-amyloid treatment referral pathway (median 5). Agreement was moderate per patient [median ICC(2,k) = 0.61] and lower for individual diagnostic-concern recommendations [median ICC(2,k) = 0.25], reflecting specialist heterogeneity on borderline non-cognitive items and ceiling effects on high-rated items.

CONCLUSION: Cognitive neurologists judged CCE-derived CDS appropriate for PCP workup and referral decisions in older adults with suspected cognitive impairment. Findings support initial content validity of assessment-linked CDS, identify refinement priorities in low-risk and emerging-therapy pathways, and motivate planned PCP appropriateness and prospective implementation studies.},
}

@article {pmid42388902,
year = {2026},
author = {Hao, Y and Yang, H and Zhong, J and Zhang, J and He, X and Dong, X},
title = {Examining of the mechanism by which Yin Huang Ge compound alleviates cognitive dysfunction in Alzheimer's disease mice through modulation of Aβ degrading enzymes and neurotrophic factors.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1821074},
pmid = {42388902},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a significant threat to human health, and with the number of patients increasing annually, developing effective prevention and treatment strategies has become an urgent priority. Early intervention is a viable strategy for treating AD, as biomarker changes associated with β-amyloid (Aβ) can emerge 20 or more years before cognitive impairment becomes apparent. Traditional Chinese medicine (TCM) offers a potential avenue for treatment at this early stage.

OBJECTIVE: This study investigated the potential therapeutic effects of the Yin Huang Ge compound on cognitive function in a mouse model of AD and evaluated its efficacy in mitigating Aβ accumulation, a key pathological feature of AD.

METHODS: APP/PS1 mice were randomly assigned to the following groups: Controls (C57BL/6 J mice) group, the Model group, YHG group, and donepezil (DNP) group. The YHG group and the DNP group were administered their respective drugs through gastric gavage, whereas the normal group and the Model group were supplied with saline. Administration sustained for a period of 30 consecutive days. We assessed mouse learning, memory, and spatial cognition using the Morris water maze, novel object recognition, Y-maze spontaneous alternation, and novel arm tests. Western blotting quantified the protein levels of β-amyloid 1-42 (Aβ1-42), insulin-degrading enzyme (IDE), neprilysin (NEP), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9). ELISA measured IDE and NEP enzymatic activity, while immunohistochemistry evaluated the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3).

RESULTS: In contrast to the Control group, mice in the Model group exhibited significant impairments in learning, memory, and spatial cognition. The protein expression levels of Aβ1-42, MMP-2, and MMP-9 were markedly elevated (p < 0.01), whereas the expression of IDE and NEP was significantly reduced (p < 0.05, p < 0.01). ELISA analysis further revealed a substantial decrease in IDE and NEP activity (p < 0.01). A concomitant reduction in the expression of NT-3 and BDNF was also observed (p < 0.01). Compared to the Model group, mice treated with YHG or DNP exhibited significantly improved learning, memory, and spatial cognition. The protein expression of Aβ1-42, MMP-2, and MMP-9 was reduced (p < 0.05, p < 0.01), whereas the expression of IDE and NEP was elevated (p < 0.05). ELISA results confirmed the increased activity of IDE and NEP (p < 0.05). These assays also revealed a marked upregulation in the expression of NT-3 and BDNF (p < 0.01).

CONCLUSION: The YHG compound reduces cerebral Aβ deposition via a bidirectional regulatory mechanism, upregulating IDE and NEP to promote clearance while downregulating MMP-2 and MMP-9 to mitigate associated damage. It also elevates the expression of the neurotrophic factors BDNF and NT-3, which enhances endogenous neuroprotection and ameliorates core Alzheimer's disease pathology. Consequently, this treatment markedly improves cognitive function in APP/PS1 mice.},
}

@article {pmid42389265,
year = {2026},
author = {Temelli Goceroglu, R and Hacimuftuoglu, A},
title = {Advances in the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1819165},
pmid = {42389265},
issn = {1663-9812},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which disease-modifying therapies remain limited. Despite extensive efforts targeting amyloid-β and tau, these approaches have not translated into clear clinical benefit, underscoring the need for a more integrated understanding of AD pathogenesis. This narrative review summarizes recent advances in the molecular mechanisms underlying AD and evaluates current and emerging therapeutic strategies. A literature search was conducted using PubMed, Google Scholar, Web of Science and Scopus, focusing on preclinical and clinical studies addressing AD pathophysiology and treatment development. Conclusion: We summarize key pathogenic pathways, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and metabolic dysregulation, and discuss how these interconnected processes have informed drug development efforts. Particular attention is given to limitations of single-target approaches and the growing interest in multi-target and combination therapies. In conclusion, a better understanding of the pathological mechanisms underlying AD may contribute to the development of more effective pharmacological therapies and integrated therapeutic approaches targeting the multifactorial nature of the disease.},
}

@article {pmid42389420,
year = {2026},
author = {Filippi, M and Cecchetti, G and Ghirelli, A and Spinelli, EG and Rugarli, G and Pisano, S and Samanes Gajate, AM and Chiti, A and Agosta, F},
title = {From Target Engagement to Treatment Governance: The Evolving Role of Amyloid PET in Anti-Amyloid Therapy.},
journal = {The Lancet regional health. Europe},
volume = {67},
number = {},
pages = {101757},
pmid = {42389420},
issn = {2666-7762},
abstract = {The introduction of anti-amyloid monoclonal antibodies has shifted Alzheimer's disease care from diagnostic clarification alone to the problem of treatment governance. While lecanemab and donanemab have demonstrated amyloid reduction at the group level, routine clinical care raises a different question: how should treatment exposure be managed in individual patients within constrained healthcare systems? We suggest that amyloid positron emission tomography (PET) may support this task by providing a quantitative baseline reference for target engagement and by informing decisions on treatment continuation, switching, or discontinuation during follow-up. However, amyloid reduction on PET should not be equated with proven individual-level clinical benefit, and the potential role of longitudinal PET must be considered alongside unresolved questions regarding safety, treatment burden, feasibility, and health-system capacity. Drawing on real-world experience from a high-volume European memory clinic, we argue that amyloid PET may have an increasingly relevant role within structured anti-amyloid treatment pathways.},
}

@article {pmid42389758,
year = {2026},
author = {Hussain, A and Alam, I and Agrawal, DK},
title = {Limitations of Current Therapies and Barriers in Alzheimer's Disease.},
journal = {Archives of internal medicine research},
volume = {9},
number = {2},
pages = {136-144},
pmid = {42389758},
issn = {2688-5654},
abstract = {Alzheimer's disease (AD) remains a major global health crisis due to its complex pathophysiology and limited therapeutic effectiveness. Despite advances in understanding key mechanisms such as amyloid-beta accumulation, tau pathology and neuroinflammation, current therapies provide limited clinical benefit. Multiple factors contribute to limitations and highlight the difficulty of translating scientific advancements into meaningful improvement in patient outcomes. This article provides a comprehensive and critical review of therapeutic, biological, clinical, and systemic barriers to effective Alzheimer's disease management as well as showcasing emerging strategies aimed to improve early detection, treatment approaches, and overall disease prevention.},
}

@article {pmid42376965,
year = {2026},
author = {Akasaka, T and Watanabe, H and Ono, M},
title = {Bithiophene Scaffold for PET Imaging and Photosensitization as a Novel Theranostic Platform Targeting Amyloid-β Aggregates.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00047},
pmid = {42376965},
issn = {1948-7193},
abstract = {Amyloid β (Aβ) aggregates are primary targets for the diagnosis and curative treatment of Alzheimer's disease (AD). While various theranostic agents targeting Aβ aggregates have been developed, most rely on fluorescent imaging, which has limited clinical translation. In contrast, nuclear medicine imaging, particularly positron emission tomography (PET), offers high sensitivity and deep tissue permeability suitable for clinical settings. Moreover, photosensitization has emerged as a promising strategy to attenuate Aβ toxicity. In this study, we designed and synthesized novel bithiophene derivatives as PET/photosensitization theranostic agents. Western blotting analysis and MALDI-TOF MS spectrometry demonstrated that FABT-2 selectively oxidized Aβ aggregates under light irradiation, leading to a significant reduction in Aβ-induced cytotoxicity, as demonstrated by CCK8 and LDH assays. Furthermore, [18]F-labeled FABT-2 showed blood-brain barrier permeability in normal mice. These results suggest that FABT-2 may be a promising lead compound for the development of theranostic agents targeting Aβ aggregates.},
}

@article {pmid42377068,
year = {2026},
author = {Cantoni, V and Grassi, M and Premi, E and Cupidi, C and Zummo, E and Cotelli, MS and Benussi, A and Borroni, B},
title = {Long-term effects of multisession gamma transcranial alternating current stimulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261461248},
doi = {10.1177/13872877261461248},
pmid = {42377068},
issn = {1875-8908},
abstract = {This study investigated the long-term clinical effects of multisession gamma transcranial alternating current stimulation (tACS) over the precuneus in early-stage Alzheimer's disease. Forty-six patients from a previous randomized, double-blind, sham-controlled trial with an open-label extension underwent follow-up at 36 and 72 weeks. Participants received either 8 or 16 weeks of gamma tACS. Both treatment durations showed comparable long-term outcomes. Alzheimer's Disease Assessment Scale-Cognitive Subscale did not significantly worsen at 36 weeks, and Face-Name Association Test remained stable at both follow-up time points, whereas Clinical Dementia Rating-Sum of Boxes and Alzheimer's Disease Cooperative Study-Activities of Daily Living worsened over time. These findings suggest relative preservation of selected cognitive measures, despite worsening in broader clinical and functional outcomes.},
}

@article {pmid42377581,
year = {2026},
author = {Terzioglu-Usak, S and Zaim, M and Beker, M and Isik, S and Elibol, B},
title = {Molecular links between reelin downregulation, topoisomerase IIβ alterations, and proteins involved in Alzheimer pathology in human SH-SY5Y neuroblastoma cell line.},
journal = {Experimental brain research},
volume = {244},
number = {8},
pages = {},
pmid = {42377581},
issn = {1432-1106},
support = {12.2016/7//Bezmialem Vakıf Üniversitesi/ ; },
mesh = {Reelin Protein ; Humans ; *Nerve Tissue Proteins/metabolism/genetics ; *Serine Endopeptidases/metabolism/genetics ; *Cell Adhesion Molecules, Neuronal/metabolism/genetics ; *Extracellular Matrix Proteins/metabolism/genetics ; Cell Line, Tumor ; *Down-Regulation/physiology ; *Alzheimer Disease/metabolism/pathology ; *DNA Topoisomerases, Type II/metabolism/genetics ; RNA, Small Interfering/metabolism/genetics ; tau Proteins/metabolism ; *DNA-Binding Proteins/metabolism/genetics ; RNA, Messenger/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Neuroblastoma/pathology ; Transfection ; Aspartic Acid Endopeptidases/metabolism ; Poly-ADP-Ribose Binding Proteins ; },
abstract = {Reelin signaling regulates multiple pathways in neurodegenerative conditions, including neuronal migration, synaptic plasticity, tau phosphorylation, and amyloidogenic processing of amyloid precursor protein (APP). This study aimed to investigate the impact of reelin downregulation on the expression of topoisomerase IIβ (topo IIβ), given its crucial role in neuronal differentiation and its established association with neurodegenerative disorders such as Alzheimer's disease (AD). Furthermore, we sought to elucidate the potential relationship between reelin downregulation and proteins implicated in the pathophysiology of AD. Firstly, the optimum concentration of small interfering RNAs (siRNA) targeting reelin was transfected into SH-SY5Y cells using Lipofectamine RNAiMAX reagent. The downregulation of reelin was confirmed at the mRNA level by real-time quantitative polymerase chain reaction (qRT-PCR). Reelin-mediated molecular alterations at both the mRNA and protein levels were analyzed by qRT-PCR and Western blotting. Reelin downregulation led to a decrease in the number of viable cells as determined by the MTT assay. Consistent with the downregulation of reelin gene expression, topo IIβ, Psen1, and BACE1 expressions were also reduced, whereas tau and APP expressions were upregulated. Although siRNA treatment effectively decreased reelin mRNA levels and the proteolytic fragment of reelin protein, no significant change was observed in total full-length reelin protein levels, suggesting the involvement of post-transcriptional regulatory mechanisms. Moreover, pTAU and APP protein expressions were increased, while Nurr1 protein was decreased in reelin-silenced cells. These findings suggest that downregulation of reelin gene expression may contribute to neurodegeneration through alterations in topo IIβ and nurr1 expression, in addition to changes in proteins associated with AD pathology.},
}

Reelin Protein
Humans
*Nerve Tissue Proteins/metabolism/genetics
*Serine Endopeptidases/metabolism/genetics
*Cell Adhesion Molecules, Neuronal/metabolism/genetics
*Extracellular Matrix Proteins/metabolism/genetics
Cell Line, Tumor
*Down-Regulation/physiology
*Alzheimer Disease/metabolism/pathology
*DNA Topoisomerases, Type II/metabolism/genetics
RNA, Small Interfering/metabolism/genetics
tau Proteins/metabolism
*DNA-Binding Proteins/metabolism/genetics
RNA, Messenger/metabolism
Amyloid beta-Protein Precursor/metabolism
Neuroblastoma/pathology
Transfection
Aspartic Acid Endopeptidases/metabolism
Poly-ADP-Ribose Binding Proteins

@article {pmid42377618,
year = {2026},
author = {Saini, D and Mujeeb, M and Akhtar, M and Haque, SE and Najmi, AK},
title = {PPAR-γ modulation restores the adiponectin-AMPK-AKT axis to attenuate metabolic stress-associated alzheimer's pathology.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42377618},
issn = {1573-4978},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *PPAR gamma/metabolism ; Male ; Rats ; Proto-Oncogene Proteins c-akt/metabolism ; Rats, Wistar ; *AMP-Activated Protein Kinases/metabolism ; Signal Transduction/drug effects ; *Adiponectin/metabolism ; Telmisartan/pharmacology ; Disease Models, Animal ; Stress, Physiological/drug effects ; Insulin Resistance ; Neuroprotective Agents/pharmacology ; Lipopolysaccharides ; Isoflavones/pharmacology ; tau Proteins/metabolism ; },
abstract = {Background Increasing evidence links metabolic dysregulation, insulin resistance, and endotoxin-induced inflammation to sporadic AD. A disruption of the PPARγ-adiponectin-AMPK-insulin pathway leads to neuroinflammation, Aβ buildup, tau hyperphosphorylation, and cognitive impairments. This study examined the neuroprotective effects of telmisartan and formononetin alone and in combination in metabolically primed AD-like rats. Methodology A two-hit model was employed to simulate metabolic endotoxemia-related sporadic Alzheimer's disease in male wistar rats. The model utilised chronic HFD feeding and systemic administration of LPS (250 µg/kg, i.p.). The animals received telmisartan, formonoetin, their combination, or a PPARγ inhibitor/ blocker. We evaluated metabolic parameters, cognitive performance, insulin resistance, inflammatory cytokines, adiponectin concentrations, cholinergic function, histopathology, and immunohistochemical markers of Aβ, tau, IRS-1, AMPK, and AKT signalling. Results The outcomes of HFD + LPS encompass weight gain, insulin resistance, inflammation, cholinergic dysfunction, neurotoxicity, elevated Aβ and tau pathology, and cognitive impairment. The therapy with telmisartan and formononetin enhanced these alterations in a dose-dependent manner, with the combination regimen demonstrating greater efficacy. The treatment reinstated adiponectin levels, enhanced AdipoR1-AMPK-AKT signalling, diminished pathogenic IRS-1 serine phosphorylation, reduced pro-inflammatory cytokines, maintained neuronal structure, and augmented recognition memory. The co-administration of PPARγ inhibitor/blocker abolished these protective effects, showing mediation reliance on PPARγ. Conclusion Telmisartan and formononetin have significant metabolic and neuroprotective advantages against AD generated by HFD and LPS through the activation of the PPARγ-adiponectin-AMPK-IRS-1-AKT signalling pathway. Targeting metabolic-inflammatory pathways using natural PPARγ modulators may aid in delaying or preventing sporadic AD associated with obesity, insulin resistance, and endotoxemia.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/pathology
*PPAR gamma/metabolism
Male
Rats
Proto-Oncogene Proteins c-akt/metabolism
Rats, Wistar
*AMP-Activated Protein Kinases/metabolism
Signal Transduction/drug effects
*Adiponectin/metabolism
Telmisartan/pharmacology
Disease Models, Animal
Stress, Physiological/drug effects
Insulin Resistance
Neuroprotective Agents/pharmacology
Lipopolysaccharides
Isoflavones/pharmacology
tau Proteins/metabolism

@article {pmid42377668,
year = {2026},
author = {Zhang, J and Zhang, Q and Jordan, JD and Zong, X},
title = {Near‑Infrared Photobiomodulation in White‑Matter Disease: From Microglial States to Measurable Endpoints.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42377668},
issn = {1559-1174},
support = {R01AG082207 and R01AG081874//National Institute on Aging of the National Institutes of Health under/ ; 149251504A//U.S. Department of Defense/ ; 24CDA1269588//American Heart Association Career Development/ ; },
mesh = {Humans ; *Microglia/radiation effects/physiology ; Animals ; *Low-Level Light Therapy/methods ; *Leukoencephalopathies/radiotherapy/diagnostic imaging/pathology ; *White Matter/radiation effects/injuries ; *Infrared Rays/therapeutic use ; Oligodendroglia/radiation effects ; Oxidative Stress ; Astrocytes/radiation effects ; Remyelination/radiation effects ; Axons/radiation effects ; },
abstract = {White-matter (WM) injury contributes to disability across multiple sclerosis, traumatic brain injury, Alzheimer's disease and related dementias, and small-vessel disease. We use microglial state programs as an organizing axis for WM injury-to-repair logic, while emphasizing that WM outcomes are multicellular and involve oligodendrocyte-lineage cells, astrocytes, axons/neurons, and vascular factors. Microglia span an injury-repair continuum, from inflammatory programs that increase oxidative stress and debris burden to repair-competent programs that support debris handling, remyelination, and axonal integrity. Near-infrared photobiomodulation (PBM; ~800-1100 nm) is most consistently associated with modulation of mitochondrial redox/bioenergetic pathways and inflammatory tone. CCO-centered mechanistic framing is best established near ~ 800-850 nm, whereas longer wavelengths (e.g., ~ 1064-1070 nm) may involve additional initiating mechanisms with downstream convergence on shared redox/bioenergetic and inflammatory pathways. Across demyelination and spinal cord injury models, appropriately dosed PBM has been reported to reduce inflammatory glial readouts and to associate with improved myelin/axon-related endpoints and functional measures, although mechanistic certainty varies across models. Human evidence remains early but broadly supports safety; a randomized trial in moderate traumatic brain injury reported treatment-related changes in diffusion-MRI WM metrics, while small dementia and chronic-injury studies report heterogeneous cognitive and physiological signals. Given dose dependence and depth-limited transcranial delivery, we synthesize mechanism-informed, dose-aware reporting guidance and WM-anchored outcome frameworks that pair diffusion MRI/DTI with interpretable biomarkers (e.g., NfL, GFAP, sTREM2) and thermally controlled sham designs. We also note potential indirect/systemic contributions that could help reconcile depth-dose constraints with deeper WM effects.},
}

Humans
*Microglia/radiation effects/physiology
Animals
*Low-Level Light Therapy/methods
*Leukoencephalopathies/radiotherapy/diagnostic imaging/pathology
*White Matter/radiation effects/injuries
*Infrared Rays/therapeutic use
Oligodendroglia/radiation effects
Oxidative Stress
Astrocytes/radiation effects
Remyelination/radiation effects
Axons/radiation effects

@article {pmid42377826,
year = {2026},
author = {Lachhab, S and Elmoussaoui, S and Rafya, M and El Mansouri, AE and Mehdi, A and Ramalhosa, RR and Costa, AR and Carreiro, EP and Andrei, G and Snoeck, R and Benkhalti, F and Sanghvi, YS and Ali, MA and Lazrek, HB},
title = {Discovery of novel perillyl and myrtenyl nucleobase conjugates as dual anti-Alzheimer and antimicrobial agents.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42377826},
issn = {1573-501X},
abstract = {Recent studies suggest that Alzheimer's disease may be influenced by microbial infections and may involve multiple microbial pathogens contributing to its development and progression. Based on this hypothesis, dual antimicrobial and anti-Alzheimer's agents may provide advantages such as improved therapeutic effectiveness, treatment of infection-related Alzheimer disease, and reduced toxicity compared with single-target drugs. To discover novel therapeutic agents, a series of terpene-substituted pyrimidine derivatives were synthesized and evaluated for their antiviral, antibacterial, antifungal and anti-Alzheimer's activities. All compounds were characterized by spectroscopic methods to support their structures. Among all compounds screened for their biological activity, compounds 11 and 32 displayed excellent IC50 values of 10.1 and 9.9 µM, respectively, against eqBChE in comparison with Food and Drug Administration (FDA)-approved drugs galantamine (IC50 = 20.6 µM) and donepezil (IC50 = 4.1 µM) for the treatment of Alzheimer's disease (AD). Additionally, compound 32 exhibited promising antifungal activity against C. tropicalis (MIC = 0.83 µmol/ml and MFC = 1.69 µmol/ml), showing two-fold greater potency than fluconazole and three-fold greater potency than 5-fluorocytosine. Moreover, terpene derivative 32 showed moderate antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis, with MIC and MBC values ranging from 3.35 to 6.71 µmol/ml. The docking studies of 32 with eqBChE supported the observed in vitro results. This study provides a promising lead compound with dual antimicrobial and anti-Alzheimer activity that may be further developed as a potential therapeutic agent for the treatment of Alzheimer's disease.},
}

@article {pmid42380069,
year = {2026},
author = {Zhang, Y and Qiao, H and Lv, Z and Guo, R and Li, D and Song, W and Wang, D},
title = {Transcranial 810 nm Pulsed Photobiomodulation Improves Learning and Reduces Aβ42 Burden in APP/PS1 Mouse Model of Alzheimer's Disease.},
journal = {Photobiomodulation, photomedicine, and laser surgery},
volume = {},
number = {},
pages = {25785478261465371},
doi = {10.1177/25785478261465371},
pmid = {42380069},
issn = {2578-5478},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of dementia in older adults, and effective and widely applicable treatment options remain limited. Photobiomodulation (PBM) has shown promise for AD. However, reported estimates of the delivered dose after transcranial propagation vary widely, limiting translation from animal models to clinical settings.

OBJECTIVE: Building on our team's prior clinical findings, this study evaluated whether an 810 nm/10 Hz pulsed PBM regimen improves cognitive performance and reduces Aβ42 burden in APP/PS1 mice.

METHODS: APP/PS1 mice received PBM using an 810 nm LED pulsed at 10 Hz. Irradiation was delivered for 540 sec/day, 6 days/week, for 7 weeks, with a scalp-surface power density of 0.025 W/cm[2] and an energy density of 13.5 J/cm[2]. Cognitive function was evaluated using the Morris water maze, and Aβ42 burden was quantified by immunofluorescence.

RESULTS: Cortical and hippocampal Aβ42 plaque burden was reduced, p < 0.01. Exploratory correlation analyses suggested an association between hippocampal Aβ42 plaque number and reversal-learning performance in the histological subset, p = 0.02. The microglia-Aβ42 colocalization ratio increased by 7.53%, p = 0.03, indicating enhanced spatial association between microglia and Aβ42 after PBM.

CONCLUSIONS: These findings support further evaluation of this 810 nm/10 Hz pulsed PBM regimen in AD mouse models and highlight the value of standardized PBM parameter reporting in preclinical studies.},
}

@article {pmid42380200,
year = {2026},
author = {Kazmi, SA and Chandra, F and Wasney, M and Cheng, J and Lum, GR and Iyer, M and Di Blasi, D and Espinoza, AN and Lopez-Romero, A and Yang, X and Garud, N and Hsiao, EY},
title = {Select microbial metabolites promote tau aggregation in a murine tauopathy model.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74775-6},
pmid = {42380200},
issn = {2041-1723},
support = {2018-191860//Silicon Valley Community Foundation (SVCF)/ ; },
abstract = {The gut microbiome is emerging as a modifier of risk for neurodegenerative diseases, but underlying mechanisms remain poorly understood. Here, we show that the hTau.P301S mouse model for progressive tauopathy develops alterations in the composition and function of the gut microbiome that are not recapitulated in amyloid-based 5xFAD or 3xTg models for Alzheimer's disease. Disrupting the gut microbiome via chronic antibiotic treatment exacerbates cognitive deficits and tau pathology in hTau.P301S mice, demonstrating a causal influence of the microbiome on tau-driven disease progression. This corresponds with widespread alterations in microbiome-dependent metabolites in the sera and brains of hTau.P301S mice, including subsets that correlate with the severity of tau pathology. By screening against tau biosensor cells, we identify select microbial metabolites-trimethylamine-N-oxide, 3-indoxyl sulfate, phenol sulfate, thymidine, and 2'deoxyuridine-that promote tau seeding and aggregation. Systemic administration of these metabolites worsens cognitive impairment and tau pathology in hTau.P301S mice. These findings establish a mechanistic link between the gut microbiome, serum and brain metabolites, as well as tau aggregation, suggesting that select microbial metabolites could potentially serve as therapeutic targets for tau-driven diseases.},
}

@article {pmid42369461,
year = {2026},
author = {Mukumbi, K and Liu, Y and Shi, Z and Liu, E and Toyli, A and Hung, GU and Chen, QH and Sha, Q and Chiu, PY and Zhou, W},
title = {Low-Density Lipoprotein Cholesterol and Dementia Risk: Integrating Mendelian Randomization and Target Trial Emulation Within the Heart-Brain Axis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.10.26355413},
pmid = {42369461},
abstract = {BACKGROUND: The heart-brain axis links cardiovascular and neurodegenerative disease through shared vascular and inflammatory mechanisms. Although low-density lipoprotein cholesterol (LDL-C) is an established causal factor in atherosclerotic cardiovascular disease (ASCVD), its relationship with dementia remains uncertain, with midlife elevations associated with increased risk but late-life associations often appearing null or inverse. To address this cholesterol paradox, we integrated mendelian randomization (MR) with an active-comparator new-user target trial emulation.

METHODS: We applied a triangulated causal inference framework integrating two-sample MR with observational target trial emulation. Genetic variants associated with LDL-C were used as instrumental variables to evaluate Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), and any dementia (AnyDem), with causal estimates derived using inverse-variance weighted models and sensitivity analyses for heterogeneity and pleiotropy. In parallel, an active-comparator new-user design compared statin versus ezetimibe initiation among adults aged ≥60 years using propensity score (PS) overlap weighting and Cox proportional hazards models to evaluate cardiovascular and dementia outcomes.

RESULTS: Genetically predicted LDL-C was associated with increased risk of DLB (OR 1.65, 95% CI 1.30-2.10; p<0.001), but not AD or AnyDem; FTD estimates were inconsistent. Sensitivity analyses suggested heterogeneity and possible pleiotropy for DLB. In the observational analysis (n=6,977), statin initiation was associated with higher risks of ASCVD (HR 1.26, 95% CI 1.11-1.45) and AnyDem (HR 1.66, 95% CI 1.16-2.38), although estimates attenuated after lipid adjustment and lagged analyses, suggesting residual confounding, treatment selection, and reverse causation in late-life observational associations.

CONCLUSIONS: These findings suggest that LDL-C reflects accumulated vascular and metabolic risk rather than a direct causal driver of AD or overall dementia, although a subtype-specific association was observed for DLB. Late-life associations appeared influenced by timing, reverse causation, and treatment selection, warranting cautious interpretation.},
}

@article {pmid42369569,
year = {2026},
author = {Liu, T and Zhang, Y and Hou, W and Hao, H and Geng, A and Zhao, G and Zhang, Y},
title = {From cellular heterogeneity to precision medicine: single-cell multi-omics in CNS disease research.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1848558},
pmid = {42369569},
issn = {1662-5102},
abstract = {Single-cell sequencing and multi-omics technologies are revolutionizing research on central nervous system (CNS) diseases by enabling high-resolution analysis of cellular heterogeneity and molecular dynamics. Traditional technologies (e.g., bulk sequencing, routine histology) often lack cellular resolution, fail to capture heterogeneity among individual cells, and struggle to reveal subtle molecular changes in early pathogenesis, limiting their ability to clarify complex CNS disease mechanisms and develop precise diagnostic tools. This review comprehensively summarizes the latest advances in single-cell multi-omics methodologies, including genomics, transcriptomics, proteomics, metabolomics, and spatial omics, and their applications in elucidating the pathogenesis, diagnosis, and treatment of common CNS disorders. Representative diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, viral meningitis, bacterial meningitis, multiple sclerosis, autism spectrum disorder, and depression are used as examples to discuss the current status and future prospects of single-cell multi-omics technologies in CNS disease research. Currently, these technologies have enabled the identification of rare pathogenic cell subsets, the mapping of cell-specific molecular pathways, and the discovery of potential diagnostic biomarkers in several common CNS disorders, though their clinical translation is still hindered by technical costs and standardization issues. In the future, the integration of single-cell multi-omics with spatial transcriptomics, artificial intelligence, and clinical data is expected to further decode the complex pathogenesis of CNS disorders, accelerate the development of targeted therapies, and promote the shift toward personalized medicine in CNS disease management-aligning with translational goals of neuropsychopharmacology.},
}

@article {pmid42370069,
year = {2026},
author = {Timashkov, A and Andreev, S and Safonova, A and Zangieva, S and Kadieva, D and Zinchenko, O},
title = {The inconsistent effects of tDCS in rehabilitation and cognitive enhancement: sources of variability and paths to personalization.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1817726},
pmid = {42370069},
issn = {1662-5161},
abstract = {BACKGROUND/AIMS: Transcranial direct current stimulation (tDCS) has emerged as a promising intervention in both rehabilitation and cognitive enhancement, yet its effects remain inconsistent across studies. This variability has raised questions about the underlying mechanisms influencing tDCS efficacy.

METHODS: In this review, we address the issue of the inconsistent effect of tDCS on motor and cognitive domains across studies in healthy individuals and those with neurodegenerative disorders. A review of literature in the field was conducted using PubMed and Google Scholar.

RESULTS: Research indicates that individual anatomical differences among subjects may contribute to the inconsistent outcomes observed, as variations in current density at targeted brain regions and genetic variations responsible for the stimulation effect. Understanding the factors that contribute to the inconsistent effects of tDCS will be essential for enhancing its application in clinical settings and maximizing its potential benefits in cognitive rehabilitation and enhancement.

CONCLUSION: Future research should focus on optimizing tDCS parameters and exploring individualized approaches to treatment, taking into account the diverse responses observed in different populations.},
}

@article {pmid42370305,
year = {2026},
author = {Maiese, K},
title = {Dementia, mood disorders, and aging: Bridging new avenues of care through shared biological pathways.},
journal = {Aging advances},
volume = {3},
number = {3},
pages = {142-151},
pmid = {42370305},
issn = {3050-6743},
abstract = {With advancing age and lifespan throughout the globe in both developed and developing nations, the risk for developing cognitive loss and mood disorders increases significantly to the extent that after reaching the age of 65, this risk almost doubles every 5 years thereafter. As a result, a corresponding rise in non-communicable diseases will impact individuals with dementia and mood disorders involving Alzheimer's disease, multiple sclerosis, depression, and anxiety. On a clinical basis, multiple risk factors and presentations that involve the loss of intellectual capacity with the onset of mental health conditions, mood disorders preceding dementia, sleep fragmentation initiation, perivascular pathway disruptions, and circadian clock dysfunction can occur in both cognitive loss and mood disorders, but a much broader scope of shared underlying cellular pathways form the underpinning for the connection of these disorders that rests upon metabolic disorders, such as diabetes mellitus. Cognitive impairment and mood disorders can precede one another as well as coexist with related co-morbidities that involve metabolic disorders with diabetes mellitus, but present treatment strategies for these disorders are primarily symptomatic in nature and rely upon disease-altering therapies that may slow disease progression but also may be accompanied by disabling complications. Given these challenges, the institution of innovative avenues is critical at this juncture to address the mutual cellular mechanisms for the treatment of disorders involving Alzheimer's disease, multiple sclerosis, depression, and anxiety. The pathways of cell senescence and telomere biology with aging, cellular metabolic dysfunction, apolipoprotein E, oxidative stress, programmed cell death with autophagy, ferroptosis, and pyroptosis, mechanistic target of rapamycin, glucagon-like peptide-1 receptor agonism, mammalian forkhead transcription factors of the "O" class, and mitochondrial dynamics offer a compelling potential to bridge these underlying pathways into unifying strategies for transition into efficacious clinical care for dementia and mood disorders. Tempered with this enthusiasm for these mutual disease mechanisms is the complexity of these pathways that will require meticulous oversight of the interdependence among pathway components and their ultimate biological impact on clinical outcomes.},
}

@article {pmid42370776,
year = {2026},
author = {Salazar, BH and Hoffman, KA and Ong, M and Welk, B and Stoffel, JT and Wood, D and Stampas, A and Khavari, R},
title = {Engineering Advances in Neurogenic Lower Urinary Tract Dysfunction (NLUTD): Current State and Future Directions - A Report From the Neurogenic Bladder Research Group (NBRG).},
journal = {Neurourology and urodynamics},
volume = {},
number = {},
pages = {},
doi = {10.1002/nau.70356},
pmid = {42370776},
issn = {1520-6777},
support = {1R13DK138734/DK/NIDDK NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVE: Neurogenic lower urinary tract dysfunction (NLUTD), stemming from neurodegenerative diseases or injuries such as cerebrovascular accidents, spinal cord injuries, and Alzheimer's disease, significantly impacts quality of life. Symptoms, including urinary frequency, urgency, incontinence, and retention, are managed with devices ranging from catheters to sacral neuromodulation. This Neurogenic Bladder Research Group (NBRG) report explores the intersection between clinical, basic science, and engineering research in personalized NLUTD treatment, identifies critical gaps for future investigation, and examines how interdisciplinary collaboration can drive engineering solutions to improve care.

METHODS: In December 2024, NBRG convened its annual meeting, gathering experts from engineering, clinical practice, research, and patient advocacy to discuss challenges in NLUTD research and explore collaborative solutions.

RESULTS: Enhanced collaboration between clinicians and engineers offers promise for improving NLUTD care. Clinicians provide critical insight into patient needs but often lack time for sustained research, while engineers contribute technical innovation yet may lack clinical exposure. Integrating patient perspectives emerged as a key theme, ensuring that technologies are practical, acceptable, and aligned with end-user needs. Discussions emphasized expanding programs that support cross-disciplinary, multi-institutional research and identifying funding pathways tailored to interdisciplinary efforts. Strategies to enhance patient involvement and foster inclusive research that reflects patient diversity and socio-demographic factors influencing care were also discussed.

CONCLUSION: Institutional support, interdisciplinary collaboration, and the active engagement of patients are key to advancing clinical care and NLUTD treatments.},
}

@article {pmid42371177,
year = {2026},
author = {Li, R and Zhang, T and Ren, D and Zhu, H and Xu, J and Xiao, L},
title = {Bushen Huoxue Acupuncture alleviates alzheimer's disease progression via the E3 ubiquitin ligase SMURF2‑mediated ubiquitination of LAPTM5.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42371177},
issn = {1573-7365},
support = {2024JJ5544//Hunan Provincial Natural Science Foundation of China/ ; },
mesh = {Animals ; *Ubiquitin-Protein Ligases/metabolism ; *Alzheimer Disease/metabolism/therapy ; *Ubiquitination/physiology ; Mice ; Microglia/metabolism ; *Acupuncture Therapy/methods ; Disease Progression ; *Membrane Proteins/metabolism ; Male ; Humans ; },
abstract = {This study investigated the therapeutic potential and mechanism of Bushen Huoxue Acupuncture (BSHXA) against Alzheimer's disease (AD) using integrated in vivo and in vitro approaches. In eight-month-old SAMP8 mice, BSHXA treatment significantly improved cognitive performance, alleviated hippocampal neuronal damage and neuroinflammation, and downregulated LAPTM5 expression. Complementary in vitro experiments in lipopolysaccharide (LPS)-stimulated BV2 microglia demonstrated that LAPTM5 knockdown reduced apoptosis, pathological protein accumulation, and pro-inflammatory M1 polarization. Through bioinformatic prediction and Co-IP assays, SMURF2 was identified as an E3 ubiquitin ligase directly interacting with LAPTM5 and promoting its ubiquitin-dependent degradation. SMURF2 overexpression in vitro reproduced protective effects similar to LAPTM5 knockdown. Importantly, in vivo knockdown of SMURF2 abolished the therapeutic benefits of BSHXA. Collectively, these findings demonstrate that BSHXA ameliorates AD progression by upregulating SMURF2, which promotes the ubiquitination and subsequent degradation of LAPTM5, thereby suppressing microglial M1 polarization, inhibiting neuroinflammatory responses, and attenuating AD pathologies. The SMURF2-LAPTM5 axis is established as a key mechanistic pathway underlying the neuroprotective effects of BSHXA.},
}

Animals
*Ubiquitin-Protein Ligases/metabolism
*Alzheimer Disease/metabolism/therapy
*Ubiquitination/physiology
Mice
Microglia/metabolism
*Acupuncture Therapy/methods
Disease Progression
*Membrane Proteins/metabolism
Male
Humans

@article {pmid42371218,
year = {2026},
author = {Kurmi, S and Parab, SB and Godad, A and Waghmare, P and Doshi, G},
title = {Neuroprotective Effects of Tenoxicam and Phenethyl Isothiocyanate in an Aβ1-42-Induced Rat Model of Alzheimer's Disease: Modulation of NF-κB/NLRP3 Signaling and Redox Homeostasis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42371218},
issn = {1559-1182},
mesh = {Animals ; Amyloid beta-Peptides/toxicity ; Male ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *NF-kappa B/metabolism ; Rats, Wistar ; *Isothiocyanates/pharmacology/therapeutic use ; *Piroxicam/analogs & derivatives/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Peptide Fragments/toxicity ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidation-Reduction/drug effects ; *Homeostasis/drug effects ; Oxidative Stress/drug effects ; Rats ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, oxidative stress, and amyloid pathology, yet effective disease-modifying therapies remain limited. This study asked whether combined targeting of inflammatory and oxidative stress pathways could offer enhanced neuroprotection in an Aβ1-42-induced rat model of AD. Tenoxicam, an oxicam-class non-steroidal anti-inflammatory drug with COX-linked anti-inflammatory activity, and phenethyl isothiocyanate (PEITC), a natural compound known for antioxidant and Nrf2-activating properties, were selected on the basis of their complementary mechanisms; however, their combined potential in this model has not been sufficiently explored, providing the rationale for this hypothesis-driven investigation. Male Wistar rats were assigned to control, disease, standard, tenoxicam, PEITC, and combination treatment groups. Cognitive performance was evaluated using the Morris Water Maze, Y-maze, and Novel Object Recognition tests, while neuroinflammatory and oxidative stress markers, including NF-κB, NLRP3, IL-1β, Nrf2, catalase, and malondialdehyde, were assessed alongside histopathological examination of hippocampal integrity and molecular docking against COX-2, NF-κB, and NLRP3. Aβ1-42 administration induced significant cognitive impairment, neuroinflammation, oxidative stress, and neuronal damage. Tenoxicam and PEITC improved behavioral performance, reduced inflammatory signaling, restored antioxidant defenses, and preserved hippocampal architecture, with the combination showing the most pronounced effects. These findings provide preclinical evidence that dual modulation of inflammatory and redox pathways may represent a promising multi-target approach for AD and support further evaluation of this combinatorial strategy.},
}

Animals
Amyloid beta-Peptides/toxicity
Male
*Alzheimer Disease/drug therapy/metabolism/pathology
*NF-kappa B/metabolism
Rats, Wistar
*Isothiocyanates/pharmacology/therapeutic use
*Piroxicam/analogs & derivatives/pharmacology/therapeutic use
*Signal Transduction/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
Disease Models, Animal
Peptide Fragments/toxicity
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Oxidation-Reduction/drug effects
*Homeostasis/drug effects
Oxidative Stress/drug effects
Rats

@article {pmid42374285,
year = {2026},
author = {Pedersen, EK and Nielsen, A and Nicolaisdóttir, DR and Øksnebjerg, L and Tannebæk, K and Janbek, J and Waldemar, G and Nielsen, TR},
title = {Associations between a psychosocial intervention and quality of life and caregiver-related outcomes in family caregivers of people with dementia: the Danish DemTool trial.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07835-7},
pmid = {42374285},
issn = {1471-2318},
abstract = {BACKGROUND: People with dementia often need comprehensive support, depending on the stage of the disease, from both family members and healthcare professionals. Caring for a person with dementia can be stressful and impact the caregiver's health and wellbeing. Studies show that family caregivers of people with dementia frequently experience stress, depression, and reduced quality of life. We aimed to assess the association between the psychosocial intervention (DemTool) and caregiver wellbeing and quality of life among family caregivers of people with dementia.

METHOD: DemTool trial was a pragmatic, cluster-controlled trial. The intervention was delivered by primary care dementia coordinators across 30 Danish municipalities from 2020 to 2023, with 15 serving as the intervention group and 15 as treatment as usual. The primary outcome measures were the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D) and the European Quality of Life Visual Analog Scale (EQ VAS). Both measures were completed at baseline and follow-up, alongside secondary quality of life outcomes. To estimate group differences in primary and secondary outcomes, we applied analysis of variance (ANOVA) and analysis of covariance (ANCOVA).

RESULTS: A total of 245 family caregivers were included in the study (181 in the intervention group and 64 in the treatment-as-usual group). Most participants were females caring for a spouse. Baseline scores for caregiver wellbeing and quality of life were similar across groups. The DemTool intervention was associated with a significant between-group difference in change from baseline in caregiver-related quality of life as measured by the Carer Experience Scale (CES), favoring the intervention. This was evident in the analysis adjusted for baseline scores (p = 0.05) and remained significant when further adjusting for caregiver-related covariates (p = 0.02). No statistically significant between-group differences were observed for the remaining wellbeing and quality-of-life outcomes.

CONCLUSION: No effects of DemTool were found on traditional health-related quality-of-life outcomes. However, a positive association was found between the intervention and the CES, underlining the importance of selecting outcomes that are directly related to the targeted effects of the intervention.

TRIAL REGISTRATION: The study protocol was registered in the ClinicalTrials.gov system, registration number: NCT07355829.},
}

@article {pmid42374501,
year = {2026},
author = {Bregman, N and de Barros, NP and Nathan, T and Levy, MH and Sima, D and Van Eyndhoven, S and Bar-David, A and Aizenstein, O and Niry, D and Atlan, L and Awad, AA and Ash, E and Omer, N and Shiner, T},
title = {Lecanemab in practice: AI-derived MRI predictors of benefit and Amyloid Related Imaging Abnormalities (ARIA).},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02127-z},
pmid = {42374501},
issn = {1758-9193},
abstract = {INTRODUCTION: Lecanemab, a monoclonal antibody targeting amyloid beta, has demonstrated meaningful clinical benefits in early Alzheimer's disease (AD), yet real-world data is needed to optimize patient selection and enhance safety monitoring, particularly with respect to amyloid-related imaging abnormalities (ARIA). Integration of quantitative and AI-derived MRI biomarkers may improve risk stratification and prediction of clinical trajectory.

METHODS: We conducted a retrospective real-world study of eighty-two patients with biomarker-confirmed early AD who initiated lecanemab at Tel Aviv Sourasky Medical Center between November 2023 and June 2025. Baseline MRI included volumetric T1-weighted imaging and susceptibility-weighted imaging (SWI). Automated whole-brain, regional cortical, and hippocampal volumes, and percentiles were extracted using FDA-cleared AI tools (icobrain by icometrix). Microhaemorrhage (MH) burden was assessed by both human and AI-assisted reads. Cognitive outcomes were evaluated using change in Mini-Mental State Examination (MMSE). Linear regression models assessed MRI predictors of cognitive response, and multivariable logistic regression identified predictors of ARIA.

RESULTS: Patients exhibited significantly lower cerebral volumes at treatment initiation. Mean whole brain percentile, mean gray-matter (GM) percentile, and mean white matter percentile were 11.45%, 8.6% and 38% respectively. Higher baseline GM volume predicted less MMSE decline at 12 months (β = 0.64, FDR-corrected p < 0.003). Hippocampal and white-matter volumes were not associated with cognitive outcomes. Seventeen patients (20.7%) developed ARIA. Baseline MH burden was the strongest predictor of ARIA (human rated OR=3.48 per MH, p=0.015, icobrain rated OR=3.25, p=0.01), while APOE ε4 carriage showed a strong directional trend which did not reach significance. Aspirin use and hypertension were not associated with ARIA. Agreement between icobrain and experts for MH ratings was excellent with a single-measure intraclass correlation coefficient (ICC) of 0.89 (95% CI: 0.83-0.93).

CONCLUSIONS: AI-derived MRI markers, particularly GM volume and MH burden, provide valuable predictors of cognitive response and ARIA risk in patients treated with lecanemab. Integrating quantitative neuroimaging into clinical workflows may enhance personalized treatment decisions and improve real-world implementation of Amyloid-targeting therapies.},
}

@article {pmid42375090,
year = {2026},
author = {Lee, HY and Hossain, MK and Jang, GH and Lee, H and Kim, YM and Chae, HJ},
title = {Behavioral and Biochemical Evaluation of a Curcumin-Loaded Nano-Liposomal Formulation in a Scopolamine-Induced Mouse Model of Cognitive Impairment.},
journal = {Biomolecules & therapeutics},
volume = {34},
number = {4},
pages = {866-881},
doi = {10.4062/biomolther.2026.062},
pmid = {42375090},
issn = {1976-9148},
abstract = {Scopolamine-induced cognitive impairment in mice models acute cholinergic dysfunction associated with early functional features of Alzheimer's disease (AD). This study evaluated the neuroprotective potential of curcumin-loaded nanoliposomes (Cur-NL), a bioavailable curcumin formulation, using behavioral, molecular, and biochemical approaches. Male mice received oral Cur-NL (250, 500, or 1000 mg/kg) for 30 days, followed by a single intraperitoneal injection of scopolamine (2 mg/kg). Cognitive performance was assessed by the open field test and Barnes maze. Acetylcholinesterase (AChE) activity, acetylcholine (ACh) levels, hippocampal gene expression, and reactive oxygen species (ROS) accumulation were analyzed to investigate underlying mechanisms. Cur-NL significantly improved spatial learning and memory and restored cholinergic balance by normalizing AChE activity and ACh levels. Treatment also attenuated hippocampal neuroinflammation, oxidative stress, and ROS accumulation. Cur-NL modulated genes related to amyloid processing and synaptic plasticity, suppressing App and Bace1 and upregulating Adam10 and Bdnf. Network analyses supported the involvement of cholinergic, inflammatory, and synaptic signaling pathways. These findings indicate that Cur-NL confers multitarget neuroprotection in a scopolamine-induced model and may serve as a candidate for managing early cholinergic-related cognitive decline. Important limitations should be acknowledged: curcumin concentrations in plasma and brain were not quantified, and a free-curcumin comparator was not included. The findings should therefore be interpreted as evidence of efficacy of the tested Cur-NL preparation, not as a comparative demonstration of nano-liposomal superiority over free curcumin. Direct pharmacokinetic and head-to-head comparative studies are required to establish the formulation-specific contribution of nano-liposomal delivery.},
}

@article {pmid42375607,
year = {2026},
author = {Lee, N and Youn, K and Kwon, H and Kim, DH and Ho, CT and Jun, M},
title = {Fucoxanthin attenuates carbonyl stress and neuroinflammation by modulating MGO/RAGE/NF-κB axis in Aβ-induced models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1811183},
pmid = {42375607},
issn = {1663-9812},
abstract = {INTRODUCTION: Amyloid-β (Aβ) accumulation is a central pathological feature of Alzheimer's disease (AD) and a major driver of disease progression. Recent evidence suggests that carbonyl stress associated with Aβ plays a critical role in AD pathology by promoting neuroinflammation and neuronal damage. In particular, methylglyoxal (MGO), a highly reactive carbonyl compound, contributes to activation of the receptor for advanced glycation end products (RAGE) and NF-κB-dependent inflammatory signaling, leading to synaptic dysfunction. The present study investigated whether fucoxanthin, a marine-derived carotenoid, attenuates Aβ-induced carbonyl stress and inflammatory responses associated with MGO/RAGE/NF-κB-related signaling.

METHODS: PC12 neuronal cells were pretreated with fucoxanthin (0.1-5 μM) and exposed to aggregated Aβ25-35 (10 μM) to assess its effects on carbonyl stress-associated inflammatory signaling. In parallel, an Aβ1-42 intracerebroventricular injection mouse model was used to validate the in vitro findings. Mice were orally administered fucoxanthin (100 or 200 mg/kg/day) for 15 days and assessed for serum MGO levels, hippocampal RAGE/NF-κB activation, microglial activation, and synaptic marker expression.

RESULTS: Fucoxanthin significantly reduced the expression of pro-inflammatory mediators, including COX-2, iNOS, IL-1β, and TNF-α in Aβ-exposed neuronal cells. This anti-inflammatory effect was associated with inhibition of NF-κB nuclear translocation and downregulation of RAGE expression. Consistent with these in vitro findings, fucoxanthin treatment in Aβ1-42-injected mice alleviated systemic and hippocampal carbonyl stress, as evidenced by decreased serum MGO levels and suppression of hippocampal RAGE/NF-κB activation. These effects were accompanied by reduced microglial activation (Iba-1) across hippocampal subregions and significant restoration of both presynaptic and postsynaptic markers, indicating preservation of synaptic integrity.

CONCLUSION: These findings demonstrate the neuroprotective role of fucoxanthin in mitigating Aβ-induced carbonyl stress by targeting the MGO/RAGE/NF-κB axis, thereby suppressing neuroinflammation and preserving synaptic integrity in Aβ-induced cellular and mouse models. Fucoxanthin emerges as a promising pharmacological candidate targeting carbonyl stress-associated mechanisms in AD.},
}

@article {pmid42376449,
year = {2026},
author = {Vukmir, RB},
title = {Alzheimer's disease and related dementia: evaluation, diagnosis and acute care management.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1743770},
pmid = {42376449},
issn = {1664-2295},
abstract = {IMPORTANCE: The patient presenting with memory loss often requires a complex, extensive multidisciplinary specialty evaluation that may begin in the primary care, emergency department, or general neurology setting. The analysis begins with a suspicion or concern regarding cognitive performance raised by the patient, family, or provider. Ideally, a better understanding will empower the primary care and general neurology communities to screen for and appropriately diagnose, treat, or refer patients with dementia.

METHODS: The thematic focus of this narrative review is diagnosis, imaging, and treatment of Alzheimer's disease and related dementia (ADRD). Information was abstracted from the National Library of Medicine MEDLINE/PubMed database. Medical Subject Headings (MeSH) heading search terms included dementia and, more specifically, Alzheimer's disease. The search targeted primary research, preferentially compared to reviews, consensus statements, or case reports if feasible.

OBSERVATIONS: Delirium typically represents an acute or subacute fluctuating change in mental status, often temporally related to acute illness. While dementia is typically associated with a more chronic progressive presentation of cognitive change without the presence of concurrent illness. However, subacute or dementia presentations may be exacerbated in that setting as well.

CONCLUSION AND RELEVANCE: The diagnosis, management, and therapy of Alzheimer's disease and related dementia is undergoing rapid change in imaging and now the utility of blood-based biomarkers. As more amyloid-modifying therapy is administered, the acute care systems should be knowledgeable of the treatment course and potential for complications.},
}

@article {pmid42261768,
year = {2026},
author = {Deng, R and Shargorodsky, A and Teopiz, K and Dri, CE and Wong, S and Le, GH and Zheng, YJ and McIntyre, RS},
title = {Lithium and long-term cognitive outcomes in bipolar disorder and early dementia: a systematic review.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e18},
doi = {10.1017/S1092852926100996},
pmid = {42261768},
issn = {2165-6509},
mesh = {Humans ; *Bipolar Disorder/drug therapy/psychology ; *Lithium Compounds/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Antimanic Agents/therapeutic use ; *Dementia/drug therapy/psychology ; Randomized Controlled Trials as Topic ; *Alzheimer Disease/drug therapy/psychology ; Cognitive Enhancement ; },
abstract = {Cognitive impairment is a major determinant of disability in bipolar disorder (BD) and a defining feature of both mild cognitive impairment (MCI) and Alzheimer's disease (AD). Lithium, a first-line maintenance treatment for BD, is implicated in neuroprotective mechanisms including glycogen synthase kinase-3β inhibition, amyloid and tau modulation, and neurogenesis promotion. The overarching aim of this systematic review is to evaluate the long-term effects of lithium on cognition across BD, MCI, and early-to-moderate AD using randomized controlled trial (RCT) evidence. Online databases were searched from inception through May 2025 for RCTs reporting lithium's effect on cognitive outcomes in BD, MCI, or early-to-moderate AD with ≥8 weeks of follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. Eight RCTs met the inclusion criteria, ranging from 10 weeks to 3 years in duration. Across four BD trials, lithium did not exhibit consistent improvement or worsening on composite cognitive scores. Three of four MCI/AD trials reported attenuated global cognitive deterioration with low-dose lithium, especially when exposure was ≥12 months. Methodological limitations included small sample sizes, exploratory endpoints, and variable measures for cognitive function as well as lithium strategies. Lithium demonstrates preliminary signals of slower cognitive decline in MCI/AD. Available evidence suggests lithium has neutral effects on cognitive impairment in BD. Future adequately powered RCTs with cognition as a primary endpoint, functional measures, and biomarker outcomes are warranted to clarify lithium's role as a maintenance treatment in psychiatric disorders and its potential neuroprotective effects in neurodegenerative diseases.},
}

Humans
*Bipolar Disorder/drug therapy/psychology
*Lithium Compounds/therapeutic use
*Cognitive Dysfunction/drug therapy
*Antimanic Agents/therapeutic use
*Dementia/drug therapy/psychology
Randomized Controlled Trials as Topic
*Alzheimer Disease/drug therapy/psychology
Cognitive Enhancement